DIQTA 1.0: Drug-Induced QT Prolongation Atlas

KETOCONAZOLE

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
QT Prolongation and Drug Interactions Leading to QT Prolongation
Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS sections.
WARNINGS
QT Prolongation and Drug Interactions Leading to QT Prolongation
Ketoconazole can prolong the QT interval. Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs which may prolong the QT interval, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes.
PRECAUTIONS
Drug Interactions
Drugs that may have their plasma concentrations increased by ketoconazole
Ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of torsade de pointes, a potentially fatal arrhythmia.
Drugs that may have their plasma concentrations increased by ketoconazole
Ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of torsade de pointes, a potentially fatal arrhythmia.
CONTRAINDICATIONS
Drug Interactions
Coadministration of a number of CYP3A4 substrates such as dofetilide, quinidine cisapride and pimozide is contraindicated with ketoconazole tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious adverse reaction may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and sometimes resulting in life-threatening ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. (See PRECAUTIONS: DRUG INTERACTIONS.)
Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS.)
CLINICAL PHARMACOLOGY
Electrocardiogram
Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT c interval. Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3 to 7 days can result in an increase of the QT c interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma concentrations about 1 to 4 hours after ketoconazole administration.
MEDICATION GUIDE
changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heart beats that can be life threatening. This can happen when ketoconazole tablets are taken with certain medicines, such as dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine. Talk to your healthcare provider about other medicines you are taking before you start taking ketoconazole tablets. Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast. These may be symptoms related to QT prolongation.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24076

Other ADRs

8461

38373126

Odds Ratio = 3.014

Drug Property Information

ATC Code(s):

J02AB02 - ketoconazole

J02AB - Imidazole derivatives
J02A - ANTIMYCOTICS FOR SYSTEMIC USE
J02 - ANTIMYCOTICS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

H02CA03 - ketoconazole

H02CA - Anticorticosteroids
H02C - ANTIADRENAL PREPARATIONS
H02 - CORTICOSTEROIDS FOR SYSTEMIC USE
H - "SYSTEMIC HORMONAL PREPARATIONS, EXCL. "

G01AF11 - ketoconazole

G01AF - Imidazole derivatives
G01A - "ANTIINFECTIVES AND ANTISEPTICS, EXCL. COMBINATIONS "
G01 - GYNECOLOGICAL ANTIINFECTIVES AND ANTISEPTICS
G - GENITO URINARY SYSTEM AND SEX HORMONES

D01AC08 - ketoconazole

D01AC - Imidazole and triazole derivatives
D01A - ANTIFUNGALS FOR TOPICAL USE
D01 - ANTIFUNGALS FOR DERMATOLOGICAL USE
D - DERMATOLOGICALS

Active Ingredient:KETOCONAZOLE

Active Ingredient UNII:R9400W927I

Drugbank ID:DB01026

PubChem Compound:3823

CTD ID:D007654

PharmGKB:PA450146

CAS Number:65277-42-1

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

200.0 mg/day J02AB02
400.0 mg/day G01AF11

Chemical Structure:

SMILE Code:
CC(=O)N1CCN(CC1)C1=CC=C(OCC2COC(CN3C=CN=C3)(O2)C2=CC=C(Cl)C=C2Cl)C=C1

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