DIQTA 1.0: Drug-Induced QT Prolongation Atlas

MEXILETINE HYDROCHLORIDE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Ambiguous

Severity Score:1.0

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

PRECAUTIONS
Drug Interactions
Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs is initiated with mexiletine, the dose of mexiletine should be slowly titrated to desired effect.
In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported. Monitoring of mexiletine plasma levels is recommended during such concurrent use to avoid ineffective therapy.
In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.
CLINICAL PHARMACOLOGY
Electrophysiology in Man
Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.
In patients with normal conduction systems, mexiletine has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third-degree AV block was observed. Mexiletine did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, mexiletine may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.
In patients with pre-existing conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24092

Other ADRs

1150

38380437

Odds Ratio = 0.0

Drug Property Information

ATC Code(s):

C01BB02 - mexiletine hydrochloride

C01BB0 -
C01BB - "Antiarrhythmics, class Ib"
C01B - "ANTIARRHYTHMICS, CLASS I AND III"
C01 - CARDIAC THERAPY
C - CARDIOVASCULAR SYSTEM

Active Ingredient:MEXILETINE HYDROCHLORIDE

Active Ingredient UNII:606D60IS38

Drugbank ID:DB00379

PubChem Compound:4178

CTD ID:D008801

PharmGKB:PA450488

CAS Number:31828-71-4

Dosage Form(s):capsule

Route(s) Of Administrator:oral

Daily Dose:

800.0 mg/day C01BB02

Chemical Structure:

SMILE Code:
CC(N)COC1=C(C)C=CC=C1C

Reference

1: Long QTc and torsades de pointes in human immunodeficiency virus disease.

[Kocheril A G,Bokhari S A,Batsford W P,Sinusas A J]
Pacing Clin Electrophysiol,1997 Nov;20(11):2810-6. PMID: 9392812

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