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DRUG RECORD

 

VENLAFAXINE

OVERVIEW
Venlafaxine

 

Introduction

Venlafaxine is a serotonin and norepinephrine reuptake inhibitor widely used as an antidepressant.  Venlafaxine 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

Venlafaxine (ven" la fax' een) is a both a serotonin and norepinephrine reuptake inhibitor, that acts by blocking the reuptake of these neurotransmitters in CNS synaptic clefts, thus increasing active levels in the brain which is associated with an antidepressant effect.  Venlafaxine was approved for use in the United States in 1995 and is still widely used with more than 17 million prescriptions filled yearly.  Current indications include major depressive disorder, generalized and social anxiety disorder, panic disorder and bipolar mood disorder.  Venlafaxine is available as tablets of 25, 37.5, 50, 75, and 100 mg and as extended release capsules of 37.5, 75 and 150 mg in multiple generic forms and under the brand name of Effexor.  The recommended dosage in adults is 75 mg daily in two or three divided doses, increasing based on tolerance and effects to a maximum of 225 mg daily.  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 less than 1% of patients on venlafaxine, 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 venlafaxine.  The onset of injury is usually within 1 to 3 months.  The patterns of serum enzyme elevation have varied from cholestatic to hepatocellular.  All cases have been self-limiting and resolved within a few months.  Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon or mild.

 

Mechanism of Injury

The mechanism by which venlafaxine causes liver injury is not known.  Venlafaxine is metabolized by the liver, mainly via the cytochrome P450 system (predominantly CYP 2D6), and hepatotoxicity may be mediated by toxic intermediates of its metabolism.  Venlafaxine can also result in significant drug-drug interactions.

 

Outcome and Management

The serum aminotransferase elevations that occur on venlafaxine therapy are usually self-limited and do not require dose modification or discontinuation of therapy.  Cases of acute and prolonged or severe liver injury have been reported in patients taking venlafaxine, but there have been no convincing instances of acute liver failure and chronic hepatitis due to venlafaxine therapy in the published literature.  Persons with intolerance to venlafaxine 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, SSRIs:  Citalopram, Escitalopram, Duloxetine, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline

 

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CASE REPORT
Venlafaxine

 

Case 1.  Acute hepatitis with jaundice due to venlafaxine.
[Modified from:  Stadlmann S, Portmann S, Tschopp S, Terracciano LM. Venlafaxine-induced cholestatic hepatitis: case report and review of literature. Am J Surg Pathol 2012; 36: 1724-8. PubMed Citation]

 

A 39 year old woman developed nausea, vomiting, pruritus and jaundice having been on oral therapy with venlafaxine for depression for two and half years but also having recently increased the dose (from 75 to 300 mg daily) 2 months previously.  She had had a cholecystectomy 20 years previously, but had no history of  chronic liver disease, alcohol use, or exposures to hepatitis.  She was mildly jaundiced and laboratory findings showed a serum bilirubin of 2.6 mg/dL, ALT 2063 U/L, and alkaline phosphatase 274 U/L.  Tests for hepatitis A, B, C and E were negative, as were tests for HIV, cytomegalovirus and Epstein Barr virus infections. Autoantibodies were not present, and abdominal ultrasound showed no evidence of biliary obstruction.  A liver biopsy showed a cholestatic hepatitis compatible with drug-induced liver injury.  Of interest, three years previously she had a similar episode of acute liver injury with jaundice that arose 3 to 4 months after increasing her dose of venlafaxine from 75 to 150 mg daily, having been on this agent for 6 years.   Upon stopping venlafaxine after the second episode, she improved minimally and serum bilirubin levels rose to 11.2 mg/dL. She was started on a course of methylprednisolone for 7 days which resulted in a prompt and lasting improvement in liver tests. 


Key Points

Medication:

Venlafaxine (300 mg daily)

Pattern:

Hepatocellular (R=25x)

Severity:

3+ (jaundice, hospitalization)

Latency:

2.5 years, 2 months after dose increase

Recovery:

Unclear

Other medications:

None mentioned

Comment

In this case, the pattern of serum enzyme elevations was hepatocellular, but symptoms and liver biopsy findings suggested a cholestatic hepatitis.  Striking in the history was a previous episode arising years after starting venlafaxine but only a few months after an increase in the daily dose.  The long latency to onset of an acute hepatitis is unusual, but a history of a change in drug dose or source of the medication is sometimes given.  Cases such as this suggest that idiosyncratic acute liver injury is not completely independent of drug dose.  

 

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PRODUCT INFORMATION
Venlafaxine

 

REPRESENTATIVE TRADE NAMES
Venlafaxine – Effexor®

 

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
Venlafaxine 93413-69-5 C17-H27-N-O2 Image of Venlafaxine Chemical Structure

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REFERENCES
Venlafaxine

 

References Last Updated:  01 December 2013

  1. Zimmerman HJ. 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; venlafaxine is not mentioned).

  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 the SNRIs is rare, venlafaxine having been implicated in occasional cases of cholestatic injury).

  3. O'Donnell JM, Shelton RC. Pharmacotherapy of 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. Schweizer E, Thielen RJ, Frazer A. Venlafaxine:a novel antidepressant compound. Expert Opin Investig Drugs 1997; 6: 65-78. PubMed Citation  (Review of the structure, pharmacology, mechanism of action, efficacy and side effects of venlafaxine; no mention of hepatotoxicity or ALT elevations).

  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. Kim KY, Hwang W, Narendran R. Acute liver damage possibly related to sertraline and venlafaxine ingestion. Ann Pharmacother 1999; 33: 381-2. PubMed Citation  (27 year old man took overdose of sertraline and cephalexin and had elevations of ALT to 1247 U/L, bilirubin 2.1 mg/dL; switched to venlafaxine but 1 week later developed abdominal pain [bilirubin 1.6 mg/dL, ALT 814 U/L], improving on stopping but relapsing 3 days after restarting sertraline; recovered fully on stopping all SSRIs).

  7. 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 among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).

  8. Horsmans Y, De Clercq M, Sernpoux C. Venlafaxine-associated hepatitis. Ann Intern Med 1999; 130: 944. PubMed Citation  (44 year old woman developed fatigue 6 months after starting venlafaxine [ALT 1082 U/L], improving over 6 months after stopping venlafaxine while continuing trazodone; no mention of bilirubin or Alk P levels).

  9. Cardona X, Avila A, Castellanos P. Venlafaxine-associated hepatitis. Ann Intern Med 1999; 130: 944. PubMed Citation  (78 year old man developed jaundice 6 weeks after starting venlafaxine [bilirubin 5.1 mg/dL, ALT 238 U/L, Alk P 680 U/L], resolving within 5 weeks of stopping).

  10. 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 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 ~1-3 per 100,000 patient-years of exposure, except for nefazodone=29/100,000).

  11. Maroy B. Hepatite aigue cytolytique apres de venlafaxine. [Acute cytolytic hepatitis after venlafaxine therapy]. Gastroenterol Clin Biol 2002; 26: 804. French. PubMed Citation  (51 year old man developed jaundice 2 months after starting venlafaxine with mild rash [bilirubin 5.8 mg/dL, ALT 73 times ULN, Alk P 2 times ULN], resolving within 2 months of stopping).

  12. 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 but SSRI liver injury has a range of presentations, although typically self-limited and with rapid recovery and without hallmarks of hypersensitivity).

  13. 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 has an excess of hepatic reports in relationship to total reports).

  14. Sencan I, Sahin I, Ozcetin A. Low-dose venlafaxine-associated liver toxicity in chronic hepatitis. Ann Pharmacother 2004; 38: 352-3. PubMed Citation  (30 year old woman with chronic hepatitis B developed ALT elevations [689 U/L] without jaundice 2 months after stopping interferon and 6 weeks after starting venlafaxine, resolving in 6 weeks; unclear whether hepatotoxicity or posttreatment flare of hepatitis B).

  15. 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%).

  16. 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; Analysis of French Pharmacovigilance data on SSRIs found 63 cases of hepatotoxicity from paroxetine, 45 fluoxetine, 30 citalopram, 18 sertraline, and 2 fluvoxamine).

  17. Phillips BB, Digmann RR, Beck MG. Hepatitis associated with low-dose venlafaxine for postmenopausal vasomotor symptoms. Ann Pharmacother 2006; 40: 323-7. PubMed Citation. (60 year old woman developed abdominal pain 1 month after starting venlafaxine [bilirubin normal, ALT 372 U/L, Alk P 758 U/L] with rapid resolution upon stopping and relapse within 6 days of restarting). 

  18. 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).

  19. 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).

  20. 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; venlafaxine not mentioned).

  21. Yildirim B, Tuncer C, Ergun M, Unal S. Venlafaxine-induced hepatotoxicity in a patient with ulcerative colitis. Ann Hepatol 2009; 8: 271-2. PubMed Citation  (55 year old man with ulcerative colitis developed fatigue and abdominal pain 2 months after starting venlafaxine [bilirubin normal, ALT 192 U/L, Alk P 419 rising to 696 U/L], resolving within 2 months of stopping).

  22. Detry O, Delwaide J, De Roover A, Hans MF, Delbouille MH, Monard J, Honore P. Fulminant hepatic failure induced by venlafaxine and trazodone therapy: a case report. Transplant Proc 2009; 41: 3435-6. PubMed Citation  (48 year old woman developed jaundice and liver failure 4 months after starting venlafaxine and trazodone [bilirubin 30 mg/dL, ALT 990 U/L, INR 4.6], undergoing liver transplantation 3 days after admission).

  23. Arroyo VC, Hallal H, Agudo JL, Aniorte JP. [Venlafaxine-induced cholestatic hepatitis]. Gastroenterol Hepatol 2009; 32: 382-3. Spanish. PubMed Citation  (39 year old man developed abdominal pain 10 days after starting venlafaxine [bilirubin rising to 18.6 mg/dL, ALT 103 U/L, Alk P 880 U/L], resolving within 5 months of stopping).

  24. 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 venlafaxine and 1 to fluoxetine but none to other SSRIs).

  25. 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). 

  26. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury 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, but none were attributed to venlafaxine despite it being one of the 50 most prescribed drugs in Iceland). 

  27. Stadlmann S, Portmann S, Tschopp S, Terracciano LM. Venlafaxine-induced cholestatic hepatitis: case report and review of literature. Am J Surg Pathol 2012; 36: 1724-8. PubMed Citation  (39 year old woman developed jaundice 2.5 years after starting and 3 months after dose increase of venlafaxine [bilirubin 4.6 mg/dL, ALT 2064 U/L, Alk P 274 U/L], with a history of a similar episode when dose was increased in the past).

  28. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. PubMed Citation  (Review of hepatotoxicity of modern antidepressants).

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OTHER REFERENCE LINKS
Venlafaxine
  1. PubMed logoRecent References on Venlafaxine

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