DIQTA 1.0: Drug-Induced QT Prolongation Atlas

METHADONE HYDROCHLORIDE

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
Life-Threatening QT Prolongation
QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone hydrochloride, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of Methadone Hydrochloride Tablets [see Warnings and Precautions (5.4)].
WARNINGS AND PRECAUTIONS
Life-Threatening QT Prolongation
Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies.
Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.
Evaluate patients developing QT prolongation while on methadone treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism.
Only initiate Methadone Hydrochloride Tablets therapy for pain in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone.
The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.
DRUG INTERACTIONS
ADVERSE REACTIONS
Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia
CLINICAL PHARMACOLOGY
Pharmacokinetics
Cytochrome P450 Inhibitors:
Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg) daily. The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed [see Drug Interactions (7)].

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

363

23729

Other ADRs

25219

38356368

Odds Ratio = 23.267

Drug Property Information

ATC Code(s):

N07BC02 - methadone hydrochloride

N07BC - Drugs used in opioid dependence
N07B - DRUGS USED IN ADDICTIVE DISORDERS
N07 - OTHER NERVOUS SYSTEM DRUGS
N - NERVOUS SYSTEM

Active Ingredient:METHADONE HYDROCHLORIDE

Active Ingredient UNII:229809935B

Drugbank ID:DB00333

PubChem Compound:4095

CTD ID:D008691

PharmGKB:PA450401

CAS Number:76-99-3

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

25.0 mg/day N07BC02

Chemical Structure:

SMILE Code:
CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

Reference

1: QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

[Wedam Erich F,Bigelow George E,Johnson Rolley E,Nuzzo Paul A,Haigney Mark C P]
Arch Intern Med,2007 Dec 10;167(22):2469-75. PMID: 18071169

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