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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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Trifluoperazine

Last Update: December 16, 2013.

OVERVIEW

Introduction

Trifluoperazine is a phenothiazine and antipsychotic agent that no longer commonly used in clinical practice. Trifluoperazine is a rare cause of clinically apparent acute cholestatic liver injury.

Background

Trifluoperazine (trye" floo oh per' a zeen) is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Trifluoperazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Trifluoperazine is indicated for the therapy of acute and chronic psychosis and rarely for nonpsychotic anxiety. Trifluoperazine was approved for use in the United States in 1959 and was formerly a commonly prescribed antipsychotic medication, but has been replaced in recent years in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Trifluoperazine is available as tablets of 1, 2, 5 and 10 mg in generic forms and formerly under the brand name of Stelazine. Oral solutions and parenteral formulations are also available. The typical recommended dose in adults in 1 to 2 mg twice daily, increasing as needed to a maximum of 6 mg daily. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Hepatotoxicity

Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury, resembling that due to chlorpromazine, have been reported with trifluoperazine therapy. The onset of jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (rash, fever and eosinophilia) were present in some cases but were mild and self-limited; autoantibodies were rare.

Mechanism of Injury

The mechanism by which phenothiazines cause serum aminotransferase elevations is not known. Several features of the clinical presentation of phenothiazine hepatotoxicity (short latency period, fever, eosinophilia) suggest a hypersensitivity reaction, and rechallenge typically causes a rapid recurrence of injury. Trifluoperazine is extensively metabolized by the liver via sulfoxidation and oxidation, and some instances of serum aminotransferase elevations as well as more clinical apparent liver injury may be caused by production of a toxic intermediate of its metabolism.

Outcome and Management

The serum aminotransferase elevations that occur on trifluoperazine therapy are usually transient and do not require dose modification or discontinuation of therapy. The acute cholestatic hepatitis caused by trifluoperazine is typically self-limited and benign. However, a proportion of cases of phenothiazine cholestatic hepatitis may be followed by prolonged jaundice and cholestasis and vanishing bile duct syndrome. Many patients with chronic cholestasis eventually improve, but they often have persistent enzyme elevations and biliary cirrhosis. No fatalities from trifluoperazine jaundice have been reported. Rechallenge with phenothiazines usually causes a prompt recurrence of the liver injury and should be avoided. Patients with trifluoperazine induced liver injury may have cross sensitivity to other phenothiazines, but generally tolerate haloperidol and the atypical antipsychotics.

Drug Class: Antipsychotic Agents

Other Drugs in the Subclass, Phenothiazines: Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Trifluoperazine – Generic, Stelazine®

DRUG CLASS

Antipsychotic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Trifluoperazine117-89-5C21-H24-F3-N3-S
Trifluoperazine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 16 December 2013

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    (Expert review of hepatotoxicity of neuroleptic drugs including the phenothiazines published in 1999; several hundred cases of chlorpromazine jaundice have been reported due to chlorpromazine, usually cholestatic, arising after 1-5 weeks, often with fever and eosinophilia, sometimes causing vanishing bile duct syndrome; other phenothiazines have only rarely been linked to liver injury, except for prochlorperazine).
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    (Review of phenothiazine hepatotoxicity mentions that liver enzyme elevations arise in up to 40% of patients taking phenothiazines and hundreds of cases of chlorpromazine jaundice have been published, frequency ~0.5-1%; onset in 2-5 weeks, usually acute cholestatic hepatitis with jaundice and pruritus; prodrome of fever and abdominal pain is common; prolonged course in 7% but usually benign; other phenothiazines have been linked to liver injury similar to that of chlorpromazine, “but with a lower frequency”).
  • Meyer JM. Pharmacotherapy of psychosis and mania. In, Brunton LL, Chabner BA, Knollman BA, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 417-56.
    (Textbook of pharmacology and therapeutics).
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    (48 year old man developed jaundice and abdominal pain 3 weeks after starting trifluoperazine [bilirubin 5.2 mg/dL, AST 95 U/L, Alk P ~10 x ULN, eosinophils 6%], resolving within 4 weeks of stopping).
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    (Review of the phenothiazines and their side effects: “Jaundice has occurred in about 1% of patients taking chlorpromazine, and also, although less frequently, in patients taking one of the more recently developed analogues”).
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    (32 year old woman and 31 year old man developed persistent jaundice [>4 years], cholestasis and liver fibrosis 3 and 4 weeks after starting chlorpromazine; acute cholestatic hepatitis evolving into chronic form with biopsies showing cirrhosis and complications of portal hypertension, most likely representing vanishing bile duct syndrome).
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    (26 year old woman developed fever, rash and pruritus 2 weeks after starting trifluoperazine [bilirubin 6.4 mg/dL, ALT 169 U/L, Alk P ~1.8 times normal, 8% eosinophils], resolving within 1 month stopping and later tolerating haloperidol without recurrence).
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    (Review of 36 biopsies from patients with phenothiazine induced liver injury from the files of the Armed Forces Institute of Pathology, 33 chlorpromazine, 3 prochlorperazine; mean onset 15 days after starting; eosinophilia in 73%, mean bilirubin 12.4 mg/dL, Alk P ~8 fold elevated, ALT 146 U/L; 6 [17%] had prolonged course for 10-16 months).
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    (Among 572 cases of drug induced liver disease seen between 1968-78 in Denmark, 51 were attributed to chlorpromazine [9%, ranking 2nd behind halothane], latency averaging 14 days [range 11-46]; 5 deaths; no other phenothiazines mentioned).
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  • Pillans PI. Drug associated hepatic reactions in New Zealand: 21 years experience. NZ Med J 1996; 109: 315-9. [PubMed: 8816722]
    (Over 21 year period in New Zealand, there were 943 reports of liver injury involving 205 drugs; chlorpromazine was in the top 20 drugs implicated accounting for 2.7% of cases; prochlorperazine was cause of 4 cases, but other phenothiazines not mentioned).
  • Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96. [PubMed: 10553730]
    (Systematic review of 81 articles on weight change with antipsychotics; using change after 10 weeks to compare agents: clozapine +5.7, olanzapine +4.2, chlorpromazine +4.2, risperidone +1.7, loxapine +0.6, haloperidol +0.5, ziprasidone +0.3, molindone -0.1, and pimozide -2.7 kilograms).
  • Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]
    (Among 126 cases of drug induced liver injury seen in Spain between 1993 and 2000, 3 were due to chlorpromazine with relative risk of 613: frequency of 261 per 100,000 person year exposures; other phenothiazines not mentioned).
  • 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, none were due to phenothiazines).
  • Flanagan RJ. Fatal toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1: 43-51. [PubMed: 18098225]
    (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).
  • 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 including 4 due to psychotropic agents; one each for quetiapine, nefazodone, fluoxetine and venlafaxine, but none for phenothiazines).
  • Sharifi V, Amini S, Ghaeli P, Saeedinia A. Trifluoperazine-induced cholestatic jaundice. Iran J Psychiatry 2010; 5: 117-8. [PMC free article: PMC3430503] [PubMed: 22952504]
    (44 year old man developed jaundice 4 weeks after starting trifluoperazine [bilirubin 3.9 mg/dL, ALT 235 U/L, Alk P 744 U/L], resolving with stopping and not recurring after switching to risperidone).
  • Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N; Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. [PMC free article: PMC3634369] [PubMed: 21788760]
    (Among 30 children with suspected drug induced liver injury, half [n=15] were due to antimicrobials [minocycline 4, INH 3, azithromycin 3] and the rest largely due to CNS agents and anticonvulsants; one case was attributed to perphenazine).

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