What is the management for a patient with a clozapine (Clozaril) overdose?

Management of Clozapine Overdose

Immediate Stabilization and Airway Management

The cornerstone of clozapine overdose management is establishing and maintaining an airway with adequate oxygenation and ventilation, as there is no specific antidote available. 1

Primary Interventions

• Secure the airway immediately and ensure adequate oxygenation and ventilation, progressing to endotracheal intubation if respiratory depression develops 1
• Monitor cardiac status and vital signs continuously from presentation, as clozapine overdose commonly causes tachycardia, hypotension, and potentially life-threatening arrhythmias 1, 2
• Contact a Certified Poison Control Center (1-800-222-1222) for expert guidance, as recommended by the FDA 1

Clinical Presentation and Risk Assessment

The most commonly reported manifestations include:

• Sedation, delirium, or coma with altered mental status 1, 2
• Cardiovascular effects: tachycardia, hypotension, and cardiac arrhythmias 1, 2
• Respiratory depression or failure requiring ventilatory support 1
• Hypersalivation and anticholinergic symptoms 1, 2
• Seizures, including potential for status epilepticus 1, 3
• Aspiration pneumonia risk due to altered mental status and hypersalivation 1

Dose-Related Considerations

• Fatal overdoses generally occur at doses above 2500 mg, though recovery has been documented with ingestions exceeding 4000 mg 1
• Plasma concentrations do not reliably predict outcome severity—a case report documented a patient with clozapine levels of 3.8 mcg/mL (normal 0.2-0.7 mcg/mL) who experienced only somnolence and mild anticholinergic effects 2

Supportive Care Protocol

Cardiovascular Management

• Administer IV fluid boluses (normal saline) for initial hypotension management 1
• Escalate to vasopressor support if hypotension persists despite fluid resuscitation—catecholamines and vasopressin are first-line agents 4
• Consider angiotensin II for refractory hypotension unresponsive to multiple vasoactive agents 4

Advanced Interventions for Refractory Cases

• Therapeutic plasma exchange (TPE) may be considered for severe, refractory hypotension despite maximal vasopressor support, as one case report demonstrated hemodynamic stabilization within 2 hours of completing TPE 4
• This represents an emerging intervention for highly protein-bound clozapine in life-threatening toxicity, though further study is needed 4

Decontamination and Enhanced Elimination

• Gastric lavage may be beneficial if performed early after ingestion, as demonstrated in cases with very high gastric concentrations 2
• General symptomatic and supportive measures should be employed, though specific decontamination protocols are not detailed in FDA labeling 1

Monitoring and Observation Period

• Maintain careful monitoring for at least 5 days to prevent late-onset complications, even in patients who initially appear stable 2
• Serial clozapine plasma levels can guide clinical decision-making, though levels typically normalize within 24 hours in uncomplicated cases 2
• Monitor for aspiration pneumonia, particularly in patients with altered mental status and hypersalivation 1

Critical Pitfalls to Avoid

• Never assume multiple-drug involvement has been ruled out—always consider the possibility of co-ingestions, particularly with other CNS depressants 1
• Do not rely solely on plasma concentrations to predict clinical severity, as outcomes vary significantly even with extremely elevated levels 2
• Avoid misdiagnosing clozapine intoxication as acute stroke, particularly in clozapine-naïve patients who may present with neurologic symptoms mimicking cerebrovascular events 3
• Recognize that infectious or inflammatory processes can precipitate clozapine toxicity even at stable therapeutic doses, requiring dose reduction and treatment of the underlying condition 5
• Do not discharge patients prematurely—extended observation is necessary even when initial presentation appears mild 2

Special Considerations

• Seizure management follows standard protocols, though clozapine lowers seizure threshold and status epilepticus may develop 3
• Anticholinergic symptoms may be managed with pyridostigmine in select cases, as documented in one case report 2
• Patients on chronic clozapine therapy require awareness that inflammation, infection, dehydration, or constipation can precipitate toxicity even without dose changes 5