DIQTA 1.0: Drug-Induced QT Prolongation Atlas

ITRACONAZOLE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:5.0

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

BOXED WARNING
Congestive Heart Failure
TOLSURA can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur or worsen during administration of TOLSURA, reassess the benefit and risk of continuing treatment [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE REACTIONS (6.1)].
[Drug Interactions]
Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs [see CONTRAINDICATIONS (4.1) and DRUG INTERACTIONS (7.1)]
Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and
Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
Increased plasma concentrations of some of these drugs caused by co-administration with TOLSURA can lead to QT prolongation and/or ventricular tachyarrhythmias, including occurrences of torsades de pointes, a potentially fatal arrhythmia [see CONTRAINDICATIONS (4.1), WARNINGS AND PRECAUTIONS (5.4) and DRUG INTERACTIONS (7.1)].
DRUG INTERACTIONS
Effect of TOLSURA on Other Drugs
Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, itraconazole has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with itraconazole.
CONTRAINDICATIONS
Drug Interactions
Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia [see DRUG INTERACTIONS (7.1)].

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24038

Other ADRs

11026

38370561

Odds Ratio = 7.818

Drug Property Information

ATC Code(s):

J02AC02 - itraconazole

J02AC - Triazole derivatives
J02A - ANTIMYCOTICS FOR SYSTEMIC USE
J02 - ANTIMYCOTICS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

Active Ingredient:Itraconazole

Active Ingredient UNII:304NUG5GF4

Drugbank ID:DB01167

PubChem Compound:55283

CTD ID:D017964

PharmGKB:PA450132

CAS Number:84625-61-6

Dosage Form(s):capsule, gelatin coated

Route(s) Of Administrator:oral

Daily Dose:

200.0 mg/day J02AC02

Chemical Structure:

SMILE Code:
CCC(C)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OC[C@H]2CO[C@@](CN3C=NC=N3)(O2)C2=CC=C(Cl)C=C2Cl)C=C1

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