DIQTA 1.0: Drug-Induced QT Prolongation Atlas

VENLAFAXINE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIQT concern

Severity Score:2.0

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

PRECAUTIONS
The electrocardiograms for 357 patients who received venlafaxine hydrochloride extended-release capsules and 285 patients who received placebo in 8 to 12 week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for venlafaxine hydrochloride extended-release capsule-treated patients 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). In these same trials, the mean change from baseline in heart rate for venlafaxine hydrochloride extended-release capsule-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine hydrochloride extended-release capsules and 1 beat per minute for placebo). In a flexible-dose study, with venlafaxine tablets, USP doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, venlafaxine tablets, USP-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.
OVERDOSAGE
Human Experience
There were 14 reports of acute overdose with venlafaxine tablets, USP, either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine tablets, USP 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 mcg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/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 events 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
Postmarketing Reports
Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, 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 events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, 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

QT Prolongation

284

23808

Other ADRs

88621

38292966

Odds Ratio = 5.155

Drug Property Information

ATC Code(s):

N06AX16 - venlafaxine

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

Active Ingredient:VENLAFAXINE HYDROCHLORIDE

Active Ingredient UNII:7D7RX5A8MO

Drugbank ID:DB00285

PubChem Compound:5656

CTD ID:D000069470

PharmGKB:PA451866

CAS Number:93413-69-5

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

100.0 mg/day N06AX16

Chemical Structure:

SMILE Code:
COC1=CC=C(C=C1)C(CN(C)C)C1(O)CCCCC1

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