DIQTA 1.0: Drug-Induced QT Prolongation Atlas

ESCITALOPRAM OXALATE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:4.0

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

DRUG INTERACTIONS
Pimozide and Celexa
In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
OVERDOSAGE
Human Experience
Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
ADVERSE REACTIONS
ECG Changes
Electrocardiograms from escitalopram oxalate (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram oxalate group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram oxalate and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram oxalate group and 0.2% in the placebo group.
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.
Investigations: bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased.
NONCLINICAL TOXICOLOGY
Cardiovascular Changes in Dogs
In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

444

23648

Other ADRs

63525

38318062

Odds Ratio = 11.326

Drug Property Information

ATC Code(s):

N06AB10 - escitalopram oxalate

N06AB - Selective serotonin reuptake inhibitors
N06A - ANTIDEPRESSANTS
N06 - PSYCHOANALEPTICS
N - NERVOUS SYSTEM

Active Ingredient:ESCITALOPRAM OXALATE

Active Ingredient UNII:5U85DBW7LO

Drugbank ID:DB01175

PubChem Compound:146570

CTD ID:D015283

PharmGKB:PA10074

CAS Number:128196-01-0

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

10.0 mg/day N06AB10

Chemical Structure:

SMILE Code:
CN(C)CCC[C@]1(OCC2=C1C=CC(=C2)C#N)C1=CC=C(F)C=C1

Reference

N/A