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DRUG RECORD

 

FLUVOXAMINE

OVERVIEW
Fluvoxamine

 

Introduction

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used in the therapy of obsessive-compulsive disorder.  Fluvoxamine 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.

 

Background

Fluvoxamine (floo vox' a meen) is a selective serotonin reuptake inhibitor (SSRI) that was developed largely for use in obsessive-compulsive disorder.  Fluvoxamine acts by blocking the reuptake of serotonin in CNS synaptic clefts, thus increasing serotonin levels in the brain which is associated with its psychiatric effects.  Fluvoxamine was approved for use in obsessive-compulsive disorder in 1994 in the United States and is used in both adults and children above the age of 8 years.  It is also used for social anxiety disorder, but not specifically for depression or bipolar disorders.  Fluvoxamine is available as tablets of 25, 50 and 100 mg in multiple generic forms and under the brand name of Luvox.  Extended release forms are also available in doses of 100 and 150 mg.  The recommended dosage in adults is 50 mg once daily, increasing to a maximum of 300 mg.  The dosage in children is 25 mg daily, increasing to a maximum of 200 to 300 mg based upon age below or above 11 years.  Common side effects are drowsiness, dyspepsia, nausea, headache, increased sweating, increased appetite, weight gain and sexual dysfunction.

 

Hepatotoxicity

Liver test abnormalities have been reported to occur in up to 1% patients on fluvoxamine, but elevations are usually modest and usually do not require dose modification or discontinuation.  A few instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with no or minimal jaundice have been reported in patients on fluvoxamine.  The onset of injury was within a few days of starting therapy and the pattern of serum enzyme elevations was hepatocellular or mixed.  Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were not mentioned.  Too few cases have been reported to characterize the clinical features of the liver injury in any detail.

 

Mechanism of Injury

The mechanism by which fluvoxamine causes liver injury is not known.  Fluvoxamine is extensively metabolized by the liver, mainly via the cytochrome P450 system, and hepatotoxicity may be mediated by toxic intermediates of their metabolism.  In addition, fluvoxamine inhibits several CYP enzymes and has signficant drug-drug interactions.

 

Outcome and Management

The serum aminotransferase elevations that occur on fluvoxamine therapy are usually self-limited and do not require dose modification or discontinuation of therapy.  No instances of acute liver failure or chronic liver injury have been attributed to fluvoxamine therapy.  Restarting fluvoxamine has been reported to cause a rapid recurrence of injury and should be avoided.  Persons with intolerance to fluvoxamine may have similar reactions to other SSRIs, and careful monitoring is warranted if other such agents are used.

 

Drug Class:  Antidepressant Agents

 

Other Drugs in the Subclass, SNRIs/SSRIs:  Citalopram, Escitalopram, Duloxetine, Fluoxetine, Levomilnacipran, Paroxetine, Sertraline, Venlafaxine, Vilazodone, Vortioxetine

 

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PRODUCT INFORMATION
Fluvoxamine

 

REPRESENTATIVE TRADE NAMES
Fluvoxamine – Generic, Luvox®

 

DRUG CLASS
Antidepressant Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Fluvoxamine 54739-18-3 C15-H21-F3-N2-O2 Image of Fluvoxamine Chemical Structure

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REFERENCES
Fluvoxamine

 

References updated:  25 March 2014

  1. Zimmerman HJ. Tricyclic antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8.  (Expert review of hepatotoxicity published in 1999 discusses several antidepressants including SSRIs but not fluvoxamine).

  2. Larrey 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. 443-62.  (Review of hepatotoxicity of antidepressants mentions that clinically apparent liver injury from fluvoxamine is rare and the clinical picture is usually hepatocellular).

  3. O'Donnell JM, Shelton RC. Drug therapy for depression and anxiety disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 397-416.  (Textbook of pharmacology and therapeutics).

  4. Lam KS, Blanchi A, Chavaillon JM. [Hepatitis probably secondary to the massive ingestion of fluvoxamine]. Gastroenterol Clin Biol 1988; 12: 398-9. PubMed Citation  (63 year old woman took an overdose of fluvoxamine [~1500 mg] and within 24 hours had elevations in ALT [1059 U/L], Alk P [668 U/L] and bilirubin [1.4 mg/dL], which remained high for more than a month).

  5. Mourilhe P, Stokes PE. Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Saf 1998; 18: 57-82. PubMed Citation  (Review of pharmacology, efficacy and safety of SSRIs; no mention of ALT elevations or hepatotoxicity).

  6. Grohmann R, Rüther E, Engel RR, Hippius H. Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRI. Pharmacopsychiatry 1999; 32: 21-8. PubMed Citation  (Analysis of reporting of adverse events among inpatients in 29 German hospitals between 1993 to 1997; 896 severe adverse events were reported among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).

  7. Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco MA, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135-7. PubMed Citation  (Analysis of cases of hepatotoxicity from antidepressants in Spanish Pharmacovigilance System from 1989-1999, identified 99 cases; among SSRIs, 26 were due to fluoxetine, 14 paroxetine, 6 fluvoxamine, 5 sertraline, 3 venlafaxine and 2 citalopram; among tricyclics, 16 clomipramine 7 amitriptyline, 6 imipramine; among miscellaneous, 3 nefazodone and 1 trazodone; but all similar in rate of occurrence estimated to be 1-3 per 100,000 patient-years of exposure, except for nefazodone=29/100,000).

  8. Lucena M, Carvajal A, Andrade R, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003; 2: 249-62. PubMed Citation  (Review of hepatotoxicity of antidepressants; antidepressant use has increased markedly between 1992 and 2002, accounting for 5% of cases of hepatotoxicity; SSRIs are less likely to cause injury than tricyclics and MAO inhibitors; range of presentations, typically self-limited and rapid recovery; no hallmarks of hypersensitivity).

  9. Spigset O, Hägg S, Bate A. Hepatic injury and pancreatitis during treatment with serotonin reuptake inhibitors: data from the World Health Organization (WHO) database of adverse drug reactions. Int Clin Psychopharmacol 2003; 18: 157-61. PubMed Citation  (Among 27,542 reports of hepatic injury in WHO database, 786 were related to SSRIs [3%], including citalopram 42, fluoxetine 222, fluvoxamine 54, paroxetine 191, sertraline 112, nefazodone 91 and venlafaxine 74; only nefazodone had an excess of hepatic reports in relationship to total reports).

  10. Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004; 37 Suppl 1: S39-45. PubMed Citation  (Analysis of adverse drug reactions reported from 1993-2000 in 35 psychiatric hospitals; 0.7% of SSRI recipients had a severe adverse event; hepatic in 0.05%).

  11. Solomons K, Gooch S, Wong A. Toxicity with selective serotonin reuptake inhibitors. Am J Psychiatry 2005; 162: 1225. PubMed Citation  (38 year old woman developed abdominal pain and ALT elevations [378 U/L] without jaundice 9 days after starting fluvoxamine; had a positive rechallenge and recurrence with citalopram [ALT 379 within 4 days], and positive rechallenge with citalopram again 1 year later).

  12. Pinzani V, Peyriere H, Hillaire-Buys D, Pageaux GP, Blayac BP, Larrey D. Specific serotonin recapture inhibitor (SSRI) antidepressants: hepatoxicity assessment in a large cohort in France. J Hepatol 2006; 44: S256.  (Abstract, not in PubMed; Analysis of French Pharmacovigilance data on SSRIs found 63 cases of hepatotoxicity from paroxetine, 45 fluoxetine, 30 citalopram, 18 sertraline, and 2 fluvoxamine).

  13. 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 Citation  (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 3 were attributed to paroxetine and 3 to fluoxetine with a relative risk of injury to rate of use in the population of 3.0 and 1.8, respectively).

  14. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007; 41: 1201-11. PubMed Citation  (Review of drug induced liver injury and reports of injury from MAO inhibitors, SSRIs, tricyclics and atypical agents).

  15. 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. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 6 were attributed to duloxetine, 3 to atomoxetine, 2 to fluoxetine, 2 to bupropion, and 1 to sertraline as single agents; no case attributed to fluvoxamine).

  16. 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. PubMed Citation  (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 1 due to fluoxetine and 1 to venalaxine but none to fluvoxamine).

  17. 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. PubMed Citation  (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 amitriptyline, but no other antidepressant was listed).

  18. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. PubMed Citation  (Review of antidepressant induced liver injury).

  19. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver iInjury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to fluvoxamine or other SSRIs, despite the fact that 5 SSRIs ranked among the top 30 most frequently prescribed drugs in Iceland).

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OTHER REFERENCE LINKS
Fluvoxamine
  1. PubMed logoRecent References on Fluvoxamine

  2. Clinical Trials logoTrials on Fluvoxamine

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