DIQTA 1.0: Drug-Induced QT Prolongation Atlas

DRONEDARONE

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

WARNINGS AND PRECAUTIONS
QT Interval Prolongation
Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see CLINICAL PHARMACOLOGY (12.2), CLINICAL STUDIES (14.1)]. If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ [see CONTRAINDICATIONS (4)].
[Renal Impairment and Failure]
Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure [see WARNINGS AND PRECAUTIONS (5.4)] or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.
DRUG INTERACTIONS
Pharmacodynamic Interactions
Drugs Prolonging the QT Interval (Inducing Torsade de Pointes)
Coadministration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of torsade de pointes–type ventricular tachycardia [see CONTRAINDICATIONS (4), CLINICAL PHARMACOLOGY (12.3)].
CONTRAINDICATIONS
MULTAQ is contraindicated in patients with:
Concomitant use of strong CYP3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see DRUG INTERACTIONS (7.2)]
Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of torsade de pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
Liver or lung toxicity related to the previous use of amiodarone
QTc Bazett interval ≥500 ms or PR interval >280 ms
ADVERSE REACTIONS
Clinical Trials Experience
In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2% vs 1.8% in the placebo group) and QT prolongation (1.5% vs 0.5% in the placebo group).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Electrophysiological Effects
Dronedarone exhibits properties of all four Vaughn-Williams antiarrhythmic classes, although it is unclear which of these are important in producing dronedarone's clinical effects. The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in healthy subjects following repeated oral doses up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. In the dronedarone 400 mg twice-daily group, there was no apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg twice daily and up to +50 ms at 1600 mg twice daily. There was a moderate dose related effect on the QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1600 mg twice daily.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24020

Other ADRs

15500

38366087

Odds Ratio = 7.42

Drug Property Information

ATC Code(s):

C01BD07 - dronedarone

C01BD - "Antiarrhythmics, class III"
C01B - "ANTIARRHYTHMICS, CLASS I AND III"
C01 - CARDIAC THERAPY
C - CARDIOVASCULAR SYSTEM

Active Ingredient:Dronedarone

Active Ingredient UNII:JQZ1L091Y2

Drugbank ID:DB04855

PubChem Compound:208898

CTD ID: D000077764

PharmGKB:PA153619853

CAS Number:141626-36-0

Dosage Form(s):tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

800.0 mg/day C01BD07

Chemical Structure:

SMILE Code:
CCCCN(CCCC)CCCOC1=CC=C(C=C1)C(=O)C1=C(CCCC)OC2=C1C=C(NS(C)(=O)=O)C=C2

Reference

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