Fluphenazine is a phenothiazine and antipsychotic agent which is no longer in common use. Fluphenazine can cause mild and transient serum enzyme elevations and has been linked to rare instances of clinically apparent cholestatic liver injury.


Fluphenazine (floo fen' a zeen) is a tricyclic aliphatic phenothiazine which acts by postsynaptic inhibition of dopamine receptors. Fluphenazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Fluphenazine was approved in the United States in 1972 for use in the therapy of acute and chronic psychosis. It was formerly a commonly prescribed antipsychotic medication, but in recent years has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Fluphenazine is currently used as parentral therapy of psychosis and is available generically in solution for depot injection. Fluphenazine was previously available under the brand name Prolixin. The typical maintenance dose in adults in 12.5 to 25 mg im or sc every 3 to 6 weeks. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain. Rare but potentially severe adverse effects include suicidal thoughts or behaviors, neuroleptic malignant syndrome and tardive dyskinesia.


Liver test abnormalities have been reported to occur in up to 40% of patients on long term therapy with phenothiazines, 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. Several instances of clinically apparent acute liver injury have been reported due to fluphenazine, which have resembled the liver injury caused by chlorpromazine and other phenothiazines. The onset of phenothiazide-related jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (fever, rash and eosinophilia) are present in some cases, but they are usually mild and self-limited; autoantibodies are rare. Most importantly, phenothiazide induced jaundice can be prolonged and associated with vanishing bile duct syndrome. All phenothiazine antipsychotic agents are probably capable of causing cholestatic liver injury, but the frequency of hepatotoxicity appears to be far greater with chlorpromazine than with others such as fluphenazine.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which fluphenazine and other phenothiazines cause serum aminotransferase elevations is not known. Many aspects 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. Fluphenazine is extensively metabolized by the liver via sulfoxidation and oxidation, and some instances of serum aminotransferase elevations as well as more clinically 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 fluphenazine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute cholestatic hepatitis caused by fluphenazine is typically self-limited and benign. While cases of prolonged jaundice and cholestasis have not been described with fluphenazine, many instances of vanishing bile duct syndrome have been attributed to other phenothiazides. Many patients with chronic cholestasis eventually improve but they often have persistent enzyme elevations and biliary cirrhosis. Fatalities from fluphenazine jaundice have not been reported. Rechallenge should be avoided. Patients with fluphenazine induced liver injury may have cross sensitivity to other phenothiazines, but generally tolerate the atypical antipsychotics.

Drug Class: Antipsychotic Agents

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



Fluphenazine – Generic, Prolixin®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 02 February 2018

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