Is Clozapine (Clozaril) Hepatotoxic?
Yes, clozapine is hepatotoxic and can cause severe, life-threatening, and even fatal liver injury including hepatic failure, hepatic necrosis, and hepatitis. 1
Incidence and Severity of Liver Toxicity
Common Transient Elevations
- Asymptomatic transaminase elevations occur in 30-60% of patients, with 15-30% experiencing elevations 2-3 times above the upper limit of normal 2, 3
- SGPT (ALT) elevation is the most frequently observed liver enzyme abnormality, occurring in 37.3% of clozapine-treated patients compared to 16.6% with haloperidol 4
- These elevations are often transient and dose-related, with approximately 60% remitting within the first 13 weeks of treatment 4
- The increase in liver enzymes appeared during the initial treatment phase in 36% of patients in a 4-year follow-up study, and normalization occurred with dose reduction 5
Serious Hepatotoxicity
- Icteric hepatitis is uncommon, occurring in approximately 0.06% of patients (84 of 136,000 patients) 3
- Fatal acute fulminant liver failure has been documented, though extremely rare at 0.001% (2 documented cases out of 136,000 patients) 3
- Severe hepatotoxicity can occur even at low to moderate doses and may involve multiple organ systems 2, 3
Risk Factors
Higher risk patients include: 4
- Male patients (significantly higher risk for SGPT elevation)
- Patients with higher clozapine plasma levels (dose-dependent relationship)
- Patients with pre-existing liver disease 1
Clinical Monitoring Requirements
FDA-Mandated Monitoring
Monitor for signs and symptoms of hepatotoxicity including: 1
- Fatigue and malaise
- Anorexia and nausea
- Jaundice
- Bilirubinemia
- Coagulopathy
- Hepatic encephalopathy
Laboratory Monitoring Strategy
- Perform serum liver function tests at baseline and regularly during treatment 1
- Increase monitoring frequency if abnormalities develop 1
- The mechanism of clozapine hepatotoxicity remains unknown, making clinical vigilance essential 3
Management of Hepatotoxicity
When to Discontinue
Permanently discontinue clozapine if: 1
- Hepatitis develops with systemic symptoms attributable to clozapine
- Transaminase elevations are combined with other systemic symptoms due to clozapine
- Signs of hepatic failure, necrosis, or severe hepatitis appear
Dose-Related Management
- Reduction of daily clozapine dose can lead to normalization of transaminase values in cases of asymptomatic elevation 5
- Most elevations are transient and resolve within 4-13 weeks, often without intervention 4
Important Clinical Caveats
- Despite the high frequency of transient asymptomatic elevations, serious hepatotoxicity is rare but potentially fatal 3
- Hepatotoxicity can develop even at low doses, as documented in case reports 2
- The hepatotoxic potential is not well recognized among many prescribers, making awareness critical 3
- With appropriate precautions concerning hepatotoxicity monitoring, clozapine can be used safely for long-term treatment in appropriately selected patients 5