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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: October 16, 2017.



Clozapine was the first atypical antipsychotic approved for treatment of schizophrenia. Because it is associated with severe and potentially fatal side effects (agranulocytosis), its use is restricted to refractory schizophrenia, and monitoring during therapy is required. Clozapine therapy is associated with serum aminotransferase elevations and in rare instances has been linked to clinically apparent acute liver injury.


Clozapine (kloe" za peen) is an atypical antipsychotic medication that appears to act both as a dopamine (D) and serotonin (5-HT2) receptor antagonist. Clozapine was introduced into clinical practice in 1971, but subsequently withdrawn in 1975 after reports of fatal agranulocytosis with its use. Nevertheless, because of its potent activity, clozapine was approved for restricted use in refractory schizophrenia in the United States in 1989 and only with surveillance using close monitoring of complete blood counts. As a result, use of clozapine has been limited. Clozapine is available as tablets of 25 and 100 mg in generic forms and under the brand names of Clozaril. The dosage of clozapine varies greatly, from 25 to as much as 900 mg daily based upon clinical response and tolerability. Common side effects include sedation, tremors, drooling, dizziness, headache, hypotension and syncope, dry mouth, constipation, and weight gain. Uncommon, but potential severe side effects include severe neutropenia, agranulocytosis, orthostatic hypotension and syncope, falls, seizures, cardiomyopathy, prolongation of the QTc interval, diabetes, dyslipidemia, weight gain and neuroleptic malignant syndrome.


Serum enzyme elevations arise in up to two-thirds of patients on clozapine but are usually modest and resolve spontaneously after 6 to 12 weeks, often not requiring dose modification or discontinuation. Occasionally, serum enzyme elevations are associated with symptoms of nausea, weakness and abdominal discomfort, and therapy should be discontinued or managed with careful dose reduction.

Acute, clinically apparent episodes of liver injury with marked liver enzyme elevations and jaundice have been reported in more than a dozen patients receiving clozapine and is estimated to occur in ~1:2000 treated patients. The onset of injury is usually within a few days to several weeks after starting, and the typical pattern of serum enzyme elevations is hepatocellular or mixed, although cholestatic cases have also been described. Severe instances of acute liver injury with progressive hepatic failure and death or need for emergency transplantation have also been described. Eosinophilia or leukocytosis are not uncommon and fever and rash have been reported, although generally mild. Autoimmune markers are rare.

Likelihood score: B (very likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which clozapine causes liver injury is not known. Clozapine is extensively metabolized by the liver, partially via the cytochrome P450 system (CYP 1A2 and others), and production of a toxic intermediate of metabolism may underlie the frequent mild serum aminotransferase elevations that occur on clozapine therapy.

Outcome and Management

The serum aminotransferase elevations that occur on clozapine therapy are often self-limited and usually do not require dose modification or discontinuation of therapy. Most instances of clinically apparent liver injury due to clozapine have been mild-to-moderate in severity and rapidly resolve. Several cases of acute liver failure due to clozapine have been reported, but there have been no instances of chronic liver disease or vanishing bile duct syndrome. Persons with intolerance to clozapine can often tolerate other atypical antipsychotic agents, such as haloperidol, risperidone, quetiapine and olanzapine.

Drug Class: Antipsychotic Agents, Atypicals



Clozapine – Generic, Clozaril®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Clozapine Chemical Structure


References updated: 16 October 2017

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    (39 year old man developed nausea, abdominal pain and jaundice after 8 weeks of clozapine therapy [bilirubin 14.7 mg/dL, ALT 1375 U/L, Alk P 290 U/L]; delay in stopping clozapine with subsequent worsening, ascites, coma and death).
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    (27 year old man developed rising ALT after 4 weeks of clozapine therapy [bilirubin 1.2 mg/dL, ALT 1325 U/L, Alk P 144 U/L] without symptoms; values normalized within 3 weeks of stopping).
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    (37 year old woman developed jaundice and sedation followed by ascites and encephalopathy 6 weeks after starting combination of valproate and clozapine [bilirubin 2.8 mg/dL, ALT 1525 U/L, high valproate levels], responding slowly to drug withdrawal; restarting clozapine was later tolerated without liver abnormalities).
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    (48 year old man developed jaundice 2 weeks after starting clozapine [bilirubin 8.7 mg/dL, ALT 100 U/L, Alk P 257 U/L], resolving within 4 weeks of switching to risperidone).
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    (30 year old man had a seizure after 4 weeks of clozapine therapy and found to have elevations in previously normal ALT [215 U/L] and Alk P [318 U/L] levels; drug stopped but time to resolution, bilirubin levels and symptoms not reported).
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    (70 year old woman given tolcapone and clozapine developed fever and stupor [ALT 71 rising to 988 U/L, CPK 531 rising to 3132 U/L, no mention of bilirubin], resolving within 10 days of stopping tolcapone, clozapine continued).
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    (Retrospective review of 233 inpatients between 1980-92; an increase in ALT in 78% of patients on clozapine and 50% on haloperidol; 3-fold increase in ALT in 15% with clozapine and 2.4% with haloperidol; lower rates of 2-fold alkaline phosphatase elevations [1% and 0.8%]).
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    (Among 23 hospitalized patients on atypical antipsychotics, 6 had ALT or AST elevations by day 14 [ALT 48-158 U/L]; 2 were on risperidone, 2 olanzapine, 1 amisulpride, none clozapine; 1 on risperidone required stopping).
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    (“Clozapine is usually reserved for treatment of patients refractory to other drugs because it causes granulocytopenia” in ~1% of patients; marked sedation and weight gain are also common; no mention of hepatotoxicity).
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    (Comparison of high doses of olanzapine vs clozapine in 8 week crossover study in 13 patients; ALT elevations in 66% of clozapine-, but in no olanzapine-treated patients; weight gain greater with olanzapine [~3.4 kg] than clozapine [~1.4 kg]).
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    (Review of the interactions of the atypical antipsychotics with the P450 system; clozapine metabolized by CYP1A2 and 3A4 and possibly 2C9 and 2D6; risperidone by CYP2D6 and possibly 3A4; olanzapine by CYP1A2 and possibly 2D6; quetiapine and ziprasidone by CYP3A4).
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    (Summary of severe adverse drug reactions reported among 35,293 inpatients; more common with atypicals [0.5-0.9%] than typical antipsychotic agents [0.02-0.2%], increased liver enzymes was most common adverse reaction to olanzapine, 4th in frequency to clozapine, 6th to haloperidol, 7th to risperidone; no mention of hepatitis or acute liver failure).
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    (46 year old woman gained 35 kg after 2 years of clozapine therapy and had ALT 100 U/L, but normal bilirubin with fatty liver on ultrasound; stopping therapy led to slow improvement in ALT; reintroduction at lower dose was tolerated without ALT elevations).
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    (27 year old man developed rise in ALT [151 U/L] without bilirubin or Alk P elevations after 2 weeks of clozapine therapy, resolved in 10 days of stopping; rechallenge led to rise in ALT to 208 U/L, biopsy showed minimal changes and lowering dose followed by improvements in ALT, allowing long term therapy).
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    (55 year old woman with onset of rash and fever 4 weeks after starting clozapine [bilirubin 1.3 mg/dL, ALT 595 U/L, Alk P 160 U/L, eosinophils rising from 3% to 31%], resolving within 1 month of stopping).
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    (Prospective study of 67 patients started on atypical antipsychotics [3 on clozapine]; ALT elevations were more frequent in 14 patients who gained >7% of body weight than in the 53 who did not [50% vs 19%] and mean changes in ALT, AST and GGT were greater; all were transient, asymptomatic and not associated with bilirubin elevations).
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    (43 year old woman developed fever 2 weeks after starting clozapine, eventually with abdominal pain, [bilirubin 0.6 mg/dL, ALT 246 U/L, Alk P 132 U/L, eosinophilia], worsening on continuing clozapine with pleural effusion and ascites, resolving with stopping drug).
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    (Review of frequency of weight gain in patients treated for bipolar disorders, most weight gain occurred with clozapine and olanzapine, but some weight gain also with quetiapine, risperidone, lithium, valproate and gabapentin; not with aripiprazole, ziprasidone, carbamazepine or lamotrigine).
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    (Thorough review of multitude of side effects of clozapine; ALT elevations occur in 30-50% of patients, usually resolving after 6-12 weeks; jaundice reported in 84 of 136,000 [0.06%] and fulminant hepatitis in 0.001%; 2 cases).
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    (Review on safety of clozapine; agranulocytosis occurred in 17 of 2260 patients [0.7%] in Finland; 50% fatality rate; ALT elevations in up to 10% of patients).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, severe antidepressants [duloxetine, sertaline, fluoxetine, amitryptilline], but none of the atypical antipsychotic agents were implicated).
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    (Controlled trial of clozapine [300 mg/day] vs ziprasidone [80-160 mg/day] for 18 weeks; similar efficacy; weight gain +0.8 kg with clozapine vs -2.6 kg with ziprasidone; “no detrimental effects for either drug were observed with regard to ...liver functions…”).
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    (Deaths from fatal poisonings decreased in England and Wales between 1993-2004, antipsychotic overdose fatalities higher for phenothiazines than atypicals; deaths/million prescriptions being 29 for chlorpromazine, 15.5 thioridazine, 3.9 trifluoperazine, 13.3 olanzapine, 21 clozapine, and 31.3 quetiapine).
  • Keane S, Lane A, Larkin T, Clarke M. Management of clozapine-related hepatotoxicity. J Clin Psychopharmacol 2009; 29: 606-7. [PubMed: 19910731]
    (Two cases; 52 year old woman developed fatigue and abdominal pain 8 days after starting clozapine [bilirubin normal, ALT 75 rising to 308 U/L, GGT 78 U/L], resolving within 4 weeks of stopping, but she was later able to tolerate long term therapy; 33 year old woman developed abnormal liver tests 5 weeks after starting clozapine [bilirubin normal, ALT 172 U/L, GGT normal], with improvement despite continuing therapy).
  • Chang A, Krygier DS, Chatur N, Yoshida EM. Clozapine-induced fatal fulminant hepatic failure: a case report. Can J Gastroenterol 2009; 23: 376-8. [PMC free article: PMC2706751] [PubMed: 19440569]
    (~40 year old woman with schizophrenia developed nausea and jaundice 6 weeks after starting clozapine which was continued to 8 weeks [bilirubin 18.8 mg/dL, ALT 1668 U/L, Alk P 273 U/L], with progressive hepatic failure and death 4 weeks later).
  • Chaplin AC, Curley MA, Wanless IR. Re: Recent case report of clozapine-induced acute hepatic failure. Can J Gastroenterol 2010; 24: 739-40; author reply 741. [PMC free article: PMC3004447] [PubMed: 21165382]
    (51 year old man developed jaundice 3 months after starting clozapine for schizophrenia [bilirubin 12.7 mg/dL, ALT 526 U/L, Alk P 1079 U/L] who died of cardiac arrest one week after presentation).
  • Gómez Espín R, Sánchez Quiles I, Hallal H, Plaza J. [Acute hepatocellular lesion after successive exposure to clozapine and olanzapine in a patient with chronic hepatitis C infection]. Gastroenterol Hepatol 2010; 33: 150-2. Spanish. [PubMed: 19914745]
    (35 year old man with chronic hepatitis C developed asymptomatic rise in ALT [188 to 723 U/L] and GGT [134 to 648 U/L] 2 months after starting clozapine, improving on stopping and recurring one month after starting olanzapine [ALT 266 to 714 U/L], resolving upon stopping again).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, olanzapine ranked 16th with 62 reports [adjusted reporting odds ratio of 3.1] and clozapine ranked 38th with 36 cases [0.8]).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 4 of which were attributed to psychotropic agents [one each due to quetiapine, nefazodone, fluoxetine and venlafaxine], but none were attributed to clozapine or olanzepine).
  • Kang SH, Lee JI. Eosinophilia, pleural effusion, hepatitis, and jaundice occurring early in clozapine treatment. Clin Psychopharmacol Neurosci 2013; 11: 103-5. [PMC free article: PMC3766753] [PubMed: 24023555]
    (47 year old woman with schizophrenia developed eosinophilia at 4 weeks, fever and myalgias at 5 weeks, and jaundice at 8 weeks after starting clozapine [bilirubin 6.0 mg/dL, ALT 254 U/L, GGT 573 U/L, eosinophils 12.9%], resolving rapidly on stopping and not recurring with olanzapine and haloperidol therapy).
  • Brown CA, Telio S, Warnock CA, Wong AH. Clozapine toxicity and hepatitis. J Clin Psychopharmacol 2013; 33: 570-1. [PubMed: 23764687]
    (48 year old woman with schizophrenia developed fatigue 4 weeks after starting clozapine [ALT 444 U/L, bilirubin, Alk P and eosinophil counts normal], resolving rapidly on stopping and not recurring on haloperidol).
  • Tucker P. Liver toxicity with clozapine. Aust N Z J Psychiatry 2013; 47: 975-6. [PubMed: 23636912]
    (21 year old man with schizophrenia developed fatigue after 3 weeks of clozapine [bilirubin 1.5 rising to 6.5 mg/dL, ALT 794 to 2282 U/L, GGT normal to 164 U/L, with leukocytosis], resolving within 4 weeks of stopping and not recurring on sulpride).
  • Nielsen J, Correll CU, Manu P, Kane JM. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry 2013; 74: 603-13. [PubMed: 23842012]
    (Systematic review of 81 studies of clozapine suggests that discontinuation of clozapine is warranted for ALT or AST elevations beyond 3 times ULN, but that dose lowering and rechallenge is sometimes possible).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to clozapine or olanzapine).
  • Kane JP, O'Neill FA. Clozapine-induced liver injury and pleural effusion. Ment Illn 2014; 6: 5403. [PMC free article: PMC4274456] [PubMed: 25553232]
    (48 year 47 year old woman with schizophrenia developed fatigue and fever [bilirubin 1.4 mg/dL, ALT 894 U/L, Alk P 220 U/L, eosinophils 2390], with worsening of abnormalities until clozapine was stopped, whereupon all tests returned to normal within 6 weeks).
  • Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, Kreutz R, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol 2015; 79: 988-99. [PMC free article: PMC4456131] [PubMed: 25444550]
    (Among 76 cases of suspected drug induced liver injury and 377 controls enrolled in a German, prospective hospital based registry, 5 cases but only 1 control were receiving clozapine [odds ratio=34.6]).
  • Wu Chou AI, Lu ML, Shen WW. Hepatotoxicity induced by clozapine: a case report and review of literature. Neuropsychiatr Dis Treat 2014; 10: 1585-7. [PMC free article: PMC4155895] [PubMed: 25210451]
    (45 year old woman with schizophrenia develop fatigue 12 days after switching from olanzapine to closapine [bilirubin normal, ALT 181 U/L, Alk P not given], resolving within 2 weeks of stopping and recurring [fever and ALT 69 U/L] at a dose of 100 mg daily).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to clozapine or olanzapine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.7%] were attributed to antipsychotic medications, including 3 to quetiapine and 2 to olanzapine, but none to clozapine).


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