OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Perphenazine – Generic, Trilafon®

DRUG CLASS

Antipsychotic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Perphenazine	58-39-9	C21-H26-Cl-N3-O-S

ANNOTATED BIBLIOGRAPHY

References updated: 01 July 2020

• Zimmerman HJ. Neuroleptic drugs. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 483-91.

  (Expert review of hepatotoxicity of neuroleptic drugs including phenothiazines published in 1999; several hundred cases of chlorpromazine jaundice have been reported, 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).
• Larry D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 447-62.

  (Review of phenothiazine hepatotoxicity mentions that 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%; similar injury can be seen with other phenothiazines but much less commonly).
• 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).
• Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet. 1965;1:175–9. [PubMed: 14238042]

  (Summary of cases of drug induced liver disease seen at Royal Free Hospital from 1959-65; 11 cases of acute liver failure including 3 due to iproniazid, 2 phenelzine, 2 phenoxypropazine, 1 prochlorperazine and 3 halogenated anesthetics; 20 cases of cholestatic hepatitis including 18 due to chlorpromazine, 1 perphenazine and 1 nitrofurantoin).
• McQueen EG. Toxic effects of phenothiazine tranquillizers. N Z Med J. 1963;62:460–2. [PubMed: 14073060]

  (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”).
• Walker CO, Combes B. Biliary cirrhosis induced by chlorpromazine. Gastroenterology. 1966;51:631–40. [PubMed: 5926937]

  (A 32 year old woman and a 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).
• Ishak KG, Irey NS. Hepatic injury associated with the phenothiazines. Clinicopathologic and follow-up study of 36 patients. Arch Pathol. 1972;93:283–304. [PubMed: 5017281]

  (Review of 36 liver biopsies of phenothiazine induced hepatotoxicity from the files of the Armed Forces Institute of Pathology; 33 due to chlorpromazine, 3 prochlorperazine; mean onset 15 days, 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).
• Døssing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol. 1982;17:205–11. [PubMed: 6982502]

  (Among 572 cases of drug induced liver disease seen between 1968-78 in Denmark, 54 were attributed to chlorpromazine [9%, ranking 2nd behind halothane], latency averaging 14 days [range 11-46]; 5 deaths; no other phenothiazine mentioned).
• Munyon WH, Salo R, Briones DF. Cytotoxic effects of neuroleptic drugs. Psychopharmacology (Berl). 1987;91:182–8. [PubMed: 2883697]

  (In vitro assay for cytotoxicity of 8 neuroleptic drugs found that chlorpromazine was more toxic than haloperidol and loxapine, but similar to other phenothiazines).
• Regal RE, Bili JE, Glazer HM. Phenothiazine-induced cholestatic jaundice. Clinical Pharmacy. 1987;6:787–94. [PubMed: 2905941]

  (Review of phenothiazine induced liver injury; cross sensitivity is rare “but does exist”).
• Pillans PI. Drug associated hepatic reactions in New Zealand: 21 years experience. N Z Med J. 1996;109:315–9. [PubMed: 8816722]

  (Over 21 year period in New Zealand, there were 943 official 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 were not mentioned).
• Gaertner I, Altendorf K, Batra A, Gaertner HJ. Relevance of liver enzyme elevations with four different neuroleptics: a retrospective review of 7,263 treatment courses. J Clin Psychopharmacol. 2001;21:215–22. [PubMed: 11270919]

  (Retrospective review of 233 psychiatric inpatients between 1980-92; any increase in ALT in 78% of patients on clozapine, 50% haloperidol and 15% perphenazine; 3-fold increase in ALT in 15% with clozapine, 2.4% with haloperidol and 1.4% perphenazine; no elevation in alkaline phosphatase with perphenazine).
• 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 1993-2000, 3 were due to chlorpromazine with relative risk of 613: frequency of 261 per 100,000 person year exposures; no other phenothiazine mentioned).
• Kane JM, Meltzer HY, Carson WH Jr, McQuade RD, Marcus RN, Sanchez R., Aripiprazole Study Group. Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin Psychiatry. 2007;68:213–23. [PubMed: 17335319]

  (Controlled trial of aripiprazole vs perphenazine in 416 adults with treatment resistant schizophrenia; the "incidence of potentially clinically significant laboratory abnormalities during the study was low" and there was no mention of ALT elevations or hepatotoxicity).
• 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).
• 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).
• 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).
• Drugs for psychiatric disorders. Treat Guidel Med Lett. 2013;11(130):53–64. [PubMed: 23715100]

  (Concise review and recommendations on use of antidepressants and antipsychotic medications including perphenazine; no discussion of hepatotoxicity).
• Marwick KF, Taylor M, Walker SW. Antipsychotics and abnormal liver function tests: systematic review. Clin Neuropharmacol. 2012;35:244–53. [PubMed: 22986798]

  (Systematic review of the literature found rates of any serum enzyme elevation during antipsychotic therapy to range from 5-78% and "clinically significant' elevations in 0-15%; does not list perphenazine).
• 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, only one of which was attributed to chlorpromazine, the only antipsychotic medication listed).
• 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 cases [0.6%] were attributed to antipsychotic agents, including 3 due to quetiapine and 2 to olanzapine, but none to perphenazine or other phenothiazines]).
• Drugs for psychotic disorders. Med Lett Drugs Ther. 2016;58(1510):160–4. [PubMed: 27960194]

  (Concise review of medications available in the US for therapy of psychotic disorders; mentions that the phenothiazines commonly cause sedation, postural hypotension and weight gain and often have extrapyramidal effects, but does not mention ALT elevations or hepatotoxicity).
• Schreiner NM, Windham S, Barker A. Atypical neuroleptic malignant syndrome: diagnosis and proposal for an expanded treatment algorithm: a case report. A A Case Rep. 2017;9:339–43. [PubMed: 28767476]

  (48 year old man with bipolar disorder and NASH underwent liver transplantation and developed confusion, dyskinesia, rigidity, hyperthermia and tachycardia/tachypnea postoperatively having been given lithium, lamotrigine, promethazine and ziprasidone, responding to therapy of neuroleptic malignant syndrome with benzodiazepines and propofol).
• Baeza I, de la Serna E, Calvo-Escalona R, Merchán-Naranjo J, Rodríguez-Latorre P, Martínez-Cantarero MC, Andrés P, et al. One-year prospective study of liver function tests in children and adolescents on second-generation antipsychotics: is there a link with metabolic syndrome? J Child Adolesc Psychopharmacol. 2018;28:463–73. [PubMed: 29975563]

  (Among 216 children and adolescents starting atypical antipsychotics, mean weight gain at 6 months was 6.5 kg and mean ALT levels increased by 8.6 U/L, while among 37 taking olanzapine mean weight gain was 10.3 kg and ALT increase 2.6 U/L, increases in ALT associated with development of the metabolic syndrome, mean ALT increasing by 27.8 U/L at 6 months).