DIRA 1.0: Atlas of Drug-induced Rhabdomyolysis

VENLAFAXINE HYDROCHLORIDE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIR concern

Severity Score:4

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

WARNINGS AND PRECAUTIONS
Use in Patients With Heart Disease
Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited.
Caution is advised in administering venlafaxine hydrochloride extended-release tablets to patients with diseases or conditions that could affect hemodynamic responses.
Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received venlafaxine hydrochloride extended-release capsules and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder as well as for 195 patients who received venlafaxine hydrochloride extended-release capsules and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). The mean change from baseline in QTc for patients treated with venlafaxine hydrochloride extended-release capsules in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for venlafaxine hydrochloride extended-release capsules and decrease of 2.0 msec for placebo).
OVERDOSAGE
Human Experience
Among the patients included in the premarketing evaluation with venlafaxine hydrochloride immediate-release tablets, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O‑desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.
In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported reactions in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
ADVERSE REACTIONS
Post-Marketing Experience
Voluntary reports of other adverse reactions temporally associated with the use of venlafaxine have been received since market introduction. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports include the following reactions: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, Takotsubo cardiomyopathy, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic reactions (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neuroleptic malignant syndrome-like reactions (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

Rhabdomyolysis

431

42481

Other ADRs

35585

14081694

Odds Ratio = 4.015

Drug Property Information

ATC Code(s):

N06AX16 - venlafaxine hydrochloride

N06AX - Other antidepressants
N06A - ANTIDEPRESSANTS
N06 - PSYCHOANALEPTICS
N - NERVOUS SYSTEM

Active Ingredient:venlafaxine hydrochloride

Active Ingredient UNII:7D7RX5A8MO

Drugbank ID:DB00285

PubChem Compound:5656

CAS Number:93413-69-5

Dosage Form(s):tablet, extended release

Route(s) Of Administrator:oral

Daily Dose:

100.0 mg/day N06AX16

Chemical Structure:

SMILE Code:
CN(C)CC(C1=CC=C(C=C1)OC)C2(CCCCC2)O

Reference

COHORT STUDY:

N/A

OTHER REFERENCE(S):

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[Fernández-Ferreiro Anxo,Pose-Reino Antonio,Martinez-Bahamonde Francisco,Paris Marion,Guemas Emilie,González-Barcia Miguel,Lamas M J]
Actas Esp Psiquiatr.2016 Sep;44(5):193-202. Epub 2016 Sep 1. PMID: 27644102

2: Rhabdomyolysis With Acute Renal Failure Requiring Dialysis in McArdle Disease: A Role for the Antidepressant Venlafaxine?

[Torner Stéphane,Tinel Claire,Soltani Zaara,Rifle Gérard,Mousson Christiane]
J Clin Psychopharmacol.2016 Aug;36(4):406-8. doi: 10.1097/JCP.0000000000000531. PMID: 27300253

3: [A fatal overdose of venlafaxine].

[Pedersen Julie Steen,Munck Lars Kristian]
Ugeskr Laeger.2014 Feb 24;176(9A):V09130539. PMID: 25350413

4: The spectrum of acute heart failure after venlafaxine overdose.

[Batista M,Dugernier T,Simon M,Haufroid V,Capron A,Fonseca S,Bonbled F,Hantson P]
Clin Toxicol (Phila).2013 Feb;51(2):92-5. doi: 10.3109/15563650.2012.763133. Epub 2013 Jan 10. PMID: 23301719

5: Low-dose venlafaxine-induced severe rhabdomyolysis: a case report.

[Huang Shiau-Shian,Yang Hsin-Yu,Lin Yu-Chen,Chan Chin-Hong]
Gen Hosp Psychiatry.2012 Jul-Aug;34(4):436.e5-7. doi: 10.1016/j.genhosppsych.2012.01.016. Epub 2012 Mar 27. PMID: 22459996

6: Venlafaxine-associated serotonin syndrome causing severe rhabdomyolysis and acute renal failure in a patient with idiopathic Parkinson disease.

[Rajapakse Senaka,Abeynaike Lakshan,Wickramarathne Thanushi]
J Clin Psychopharmacol.2010 Oct;30(5):620-2. doi: 10.1097/JCP.0b013e3181ee2ae7. PMID: 20814334

7: Venlafaxine ingestion is associated with rhabdomyolysis in adults: a case series.

[Wilson A D,Howell C,Waring W S]
J Toxicol Sci.2007 Feb;32(1):97-101. PMID: 17327698

8: Neuroleptic malignant syndrome after the use of venlafaxine in a patient with generalized anxiety disorder.

[Lu Tsung-Chien,Chu Pei-Lun,Wu Chi-Shin,Tsai Kuang-Chau,Chen Wen-Jone]
J Formos Med Assoc.2006 Jan;105(1):90-3. PMID: 16440077

9: Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report.

[Hanekamp B B,Zijlstra J G,Tulleken J E,Ligtenberg J J M,van der Werf T S,Hofstra L S]
Neth J Med.2005 Sep;63(8):316-8. PMID: 16186642

10: Severe rhabdomyolysis following venlafaxine overdose.

[Pascale Patrizio,Oddo Mauro,Pacher Pal,Augsburger Marc,Liaudet Lucas]
Ther Drug Monit.2005 Oct;27(5):562-4. PMID: 16175126

11: Venlafaxine poisoning complicated by a late rise in creatine kinase: two case reports.

[Oliver J J,Kelly C,Jarvie D,Denieul S,Bateman D N]
Hum Exp Toxicol.2002 Aug;21(8):463-6. PMID: 12412641

12: Seizures, ventricular tachycardia, and rhabdomyolysis as a result of ingestion of venlafaxine and lamotrigine.

[Peano C,Leikin J B,Hanashiro P K]
Ann Emerg Med.1997 Nov;30(5):704-8. PMID: 9360588

13: Serotonin syndrome from venlafaxine-tranylcypromine interaction.

[Brubacher J R,Hoffman R S,Lurin M J]
Vet Hum Toxicol.1996 Oct;38(5):358-61. PMID: 8888541

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