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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Venlafaxine, Desvenlafaxine

Last Update: March 6, 2020.

OVERVIEW

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 16 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, 100 and 150 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. Uncommon but potentially severe adverse events include suicidal thoughts and behaviors, serotonin syndrome, activation of mania, hypertension, abnormal bleedings and angle-closure glaucoma.

Desvenlafaxine (des” ven la fax' een) is the major active metabolite of venlafaxine and has been marketed separately as a serotonin and norepinephrine reuptake inhibitor. Desvenlafaxine is believed to act by blocking the reuptake of neurotransmitters in CNS synaptic clefts, thus increasing active levels in the brain which is associated with an antidepressant effect. Desvenlafaxine was approved for use in the United States in 2008 and is still used with more than 1 million prescriptions filled yearly. Current indications are limited to major depressive disorder. There is little evidence to suggest that it is more effective or has a different spectrum or rate of adverse events as venlafaxine. Desvenlafaxine is available as extended release tablets of 25, 50, or 100 mg in generic forms and under the brand name of Pristiq. The recommended dosage in adults is 50 mg once daily; increasing the dose has not been shown to improve efficacy. While believed to be better tolerated than venlafaxine, desvenlafaxine appears to have a similar spectrum and frequency of side effects.

Hepatotoxicity

Liver test abnormalities have been reported to occur in less than 1% of patients on venlafaxine or desvenlafaxine, 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 both venlafaxine but not desvenlafaxine, perhaps because of less overall use of the more recently approved agent. 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. The estimated frequency is 1 per 5000 patients years of exposure.

Likelihood score (venlafaxine): B (highly likely rare causes of clinically apparent liver injury).

Likelihood score (desvenlafaxine): E* (suspected but unproven cause of clinically apparent liver injury).

Mechanism of Injury

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

Outcome and Management

The serum aminotransferase elevations that occur on venlafaxine and desvenlafaxine 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 receiving venlafaxine, but there have been no convincing instances of acute liver failure due to venlafaxine or desvenlafaxine therapy in the published literature. Persons with intolerance to venlafaxine or desvenlafaxine may have similar reactions to each other as well as 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, Fluvoxamine, Levomilnacipran, Paroxetine, Sertraline, Vilazodone, Vortioxetine

CASE REPORT

Case 1. Acute hepatitis with jaundice due to venlafaxine.(1)

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=25)
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.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Venlafaxine – Generic, Effexor®

Desvenlafaxine – Generic, Pristiq®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING (Venlafaxine)

COMPLETE LABELING (Desvenlafaxine)

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Venlafaxine 93413-69-5 C17-H27-N-O2 image 135015286 in the ncbi pubchem database
Desvenlafaxine 93413-62-8 C16-H25-N-O2 image 135080249 in the ncbi pubchem database

CITED REFERENCE

1.
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: 23073329]

ANNOTATED BIBLIOGRAPHY

References updated: 06 March 2020

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    (55 year old man developed nausea, tachycardia and high lactate levels within hours of taking an overdose of venlafaxine [lactate 8.6 mmol/L, pH 7.39] with normal liver tests, resolving within 24 hours with hydration and medical support).
  • Poitras V, Visintini S. Desvenlafaxine versus venlafaxine for the treatment of adult patients with major depressive disorder: a review of the comparative clinical and cost-effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Oct 25. Available from http://www​.ncbi.nlm.nih​.gov/books/NBK507133/ [PubMed: 29889482]
    (Review of systematic reviews on the comparison of the efficacy of desvenlafaxine and venlafaxine concluded that the two agents were similar in effectiveness).
  • Ferrajolo C, Scavone C, Donati M, Bortolami O, Stoppa G, Motola D, Vannacci A, et al. DILI-IT Study Group. Antidepressant-induced acute liver injury: a case-control study in an Italian inpatient population. Drug Saf. 2018;41:95–102. [PubMed: 28770534]
    (Among 179 cases of hospitalizations for unexplained acute liver injury enrolled in an Italian prospective study between 2010 and 2014, 17 had been exposed to antidepressants including citalopram [n=4], sertraline [n=3], amitriptyline [n=3] and paroxetine [n=2], but venlafaxine was not implicated in any case).
  • Billioti de Gage S, Collin C, Le-Tri T, Pariente A, Bégaud B, Verdoux H, Dray-Spira R, et al. Antidepressants and hepatotoxicity: A cohort study among 5 million individuals registered in the French National Health Insurance Database. CNS Drugs. 2018;32:673–84. [PMC free article: PMC6061298] [PubMed: 29959758]
    (Among 5 million persons identified in a national French health insurance database who started an antidepressant between 2010 and 2015, 382 developed serious liver injury resulting in hospitalization, rates per 100,0000 persons-years being 19 for SSRIs, 22 venlafaxine, 13 duloxetine, and 33 mirtazapine).
  • Atkinson S, Lubaczewski S, Ramaker S, England RD, Wajsbrot DB, Abbas R, Findling RL. Desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder. J Child Adolesc Psychopharmacol. 2018;28:55–65. [PMC free article: PMC5771531] [PubMed: 29185786]
    (Among 363 children with major depression treated with desvenlafaxine in two doses or placebo for 8 weeks, there were no changes in depression rating scores and side effect rates were similar in all groups, mean ALT, AST and Alk P levels not changing significantly).
  • Atkinson S, Thurman L, Ramaker S, Buckley G, Jones SR, England R, Wajsbrot D. Safety, tolerability, and efficacy of desvenlafaxine in children and adolescents with major depressive disorder: results from two open-label extension trials. CNS Spectr. 2019;24:496–506. [PubMed: 30419989]
    (Analysis and comparison of two 6-month open-label trials of desvenlafaxine in 552 children and adolescents with major depression found no new safety signals; no discussion of ALT elevations or hepatotoxicity).

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