Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used as an antidepressant. Fluoxetine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.
Fluoxetine (floo ox' e teen) is an antidepressant which was one of the first of the class of selective serotonin reuptake inhibitors (SSRIs) introduced into clinical use. By blocking the reuptake of serotonin in CNS synaptic clefts, SSRIs increase serotonin levels in the brain which is associated with their antidepressant effect. Fluoxetine was approved for use in the United States in 1987 and it has become one of the most widely used antidepressant medications, more than 20 million prescriptions being written yearly. Current indications include major depressive disorders, panic and obsessive compulsive disorders, bulemia nervosa and bipolar illness in combination with other agents. Fluoxetine is available as tablets and capsules of 10, 20 and 40 mg and in an oral solution of 20 mg/5 mL, in multiple generic forms and under the brand names of Prozac and Sarafem. Fixed combinations of fluoxetine with olanzapine (Symbyax and generic forms) are also available. A long acting formulation of 90 mg of fluoxetine has been developed for once weekly dosing (Prozac weekly). The recommended dosage of standard formulations of fluoxetine in adults is 20 mg once daily, increasing to 40 mg daily if necessary and not exceeding 80 mg daily. Common side effects are drowsiness, dyspepsia, nausea, headache, increased sweating, increased appetite, weight gain and sexual dysfunction.
Liver test abnormalities have been reported to occur rarely in patients on fluoxetine (less than 1%), and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on fluoxetine. The onset of injury is usually within 2 to 12 weeks and the pattern of serum enzyme elevations is usually hepatocellular, but convincing cases of mixed and cholestatic injury have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.
Mechanism of Injury
The mechanism by which fluoxetine causes liver injury is not known. Fluoxetine is extensively metabolized by the liver, mainly via the cytochrome P450 system, and hepatotoxicity may be mediated by toxic intermediates of their metabolism.
Outcome and Management
The serum aminotransferase elevations that occur on fluoxetine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. Rare instances of acute liver failure and chronic hepatitis have been attributed to fluoxetine therapy. Persons with intolerance to fluoxetine may have similar reactions to other SSRIs and careful monitoring is warranted if other such agents are used.
Case 1. Acute cholestatic hepatitis due to fluoxetine.
[Modified from: Cosme A, Barrio J, Lobo C, Gil Y, Castiella A, Arenas JI. Acute cholestasis by fluoxetine. Am J Gastroenterol 1996; 91: 2449-50. PubMed Citation]
A 49 year old man with depression developed jaundice five months after starting fluoxetine (20 mg daily), sulpiride (100 mg daily) and diazepam (10 mg daily). He had no history of liver disease or jaundice, but drank an estimated 38 grams of alcohol (~3-4 drinks) daily. He was taking no other medications. Physical examination showed jaundice but no fever or rash. Laboratory testing showed bilirubin of 13.6 mg/dL (direct 11.6 mg/dL), modest elevations in serum aminotransferase levels (ALT 88 U/L; AST 188 U/L), but marked increases in alkaline phosphatase (682 U/L) and gamma glutamyl transpeptidase levels (1,560 U/L) (Table). Tests for hepatitis A, B and C were negative as were autoantibodies. Abdominal ultrasound, CT scans and ERCP showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis, mild portal inflammation, and isolated single hepatocyte necrosis. Fluoxetine was stopped, and he began to improve quickly. In follow up 40 days later, laboratory tests were normal.
|Pattern:|| Cholestatic (R=0.9)|
||3+ (jaundice, hospitalization)
|Other medications:||Sulpiride, diazepam|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
|Fluoxetine taken for 5 months
The selective serotonin reuptake inhibitors (SSRIs) are some of the most commonly used prescription medications worldwide, yet reports of clinically apparent hepatic injury during their use are rare. Typically, the latency to onset is 1 to 6 months and the pattern of injury is either an acute hepatocellular or cholestatic hepatitis that is self-limited and rapidly reversed upon withdrawal of the agent. Sulpiride is substituted benzamide, an antipsychotic medication used in Europe but not available in the United States; it has not been clearly implicated in cases of drug induced liver injury. When patients develop clinically apparent liver injury from an SSRI, it is not clear whether another member of this group can be substituted. A structurally unrelated substitute along with careful monitoring is perhaps prudent if antidepressant therapy is considered necessary.
REPRESENTATIVE TRADE NAMES
Fluoxetine – Prozac®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 26 March 2014
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Mars F, Dumas de la Roque G, Goissen P. [Acute hepatitis during treatment of fluoxetine]. Gastroenterol Clin Biol 1991; 15: 270-1. French. PubMed Citation (38 year old woman with severe mitral insufficiency developed fever and weakness 7 months after starting fluoxetine [bilirubin normal, ALT 444 U/L], resolving within one month of stopping therapy).
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Cosme A, Barrio J, Lobo C, Gil Y, Castiella A, Arenas JI. Acute cholestasis by fluoxetine. Am J Gastroenterol 1996; 91: 2449-50. PubMed Citation (49 year old man developed jaundice 5 months after starting fluoxetine [bilirubin 13.6 mg/dL, ALT 88 U/L, Alk P 682 U/L], improving within 1-2 months of stopping).
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Cai Q, Benson MA, Talbot TJ, Devadas G, Swanson HJ, Olson JL, Kirchner JP. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999; 74: 692-4. PubMed Citation (Two cases of fluoxetine hepatotoxicity; 39 year old man developed jaundice 1-2 years after starting fluoxetine [bilirubin 5.9 mg/dL, ALT 272 U/L, Alk P 153 U/L], resolving within 4-6 months of stopping; 45 year old woman with jaundice arising after 3 months of fluoxetine [bilirubin 6.4 mg/dL, ALT 641 U/L, Alk P 210 U/L], resolving within 2 months of stopping).
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