Mexiletine and Propafenone: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Mexiletine
Propafenone
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
An increased risk of mexiletine toxicity (cardiac arrhythmia)
Interaction Deep Dive
Propafenone is a potent cytochrome P450 2D6 (CYP2D6) inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates, such as mexiletine. Coadministration of propafenone to extensive metabolizers decreased oral clearance of R-(-)-mexiletine (41 +/- 11 L/h to 28 +/- 7 L/h) and S-(+)-mexiletine (from 43 +/- 15 L/h to 29 +/- 11 L/h) to an extent such that these values were similar to those measured in poor metabolizers. Coadministration of propafenone to extensive metabolizers decreased by 71%, 67%, and 73% the partial metabolic clearances of mexiletine to hydroxymethylmexiletine, m-hydroxymexiletine, and p-hydroxymexiletine, respectively. Only the partial metabolic clearance of mexiletine to hydroxymethylmexiletine was significantly decreased by the administration of propafenone. Patients with underlying cardiac ischemic disease may be predisposed to proarrhythmia due to potentiation of drug effects1.
Why it happens (mechanism)
Inhibition by propafenone of CYP450 2D6-dependent metabolic pathways of mexiletine
Literature reports
1 report — tap to read
a) Propafenone is a potent cytochrome P450 2D6 (CYP2D6) inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates, such as mexiletine. Mexiletine 100 mg twice daily was given to 15 healthy volunteers (8 extensive metabolizers and 7 poor metabolizers of CYP2D6) from day 1 to day 8. Oral propafenone 150 mg twice daily was administered from day 5 to day 12. Elimination of mexiletine was significantly impaired with concomitant administration of propafenone due to inhibition of CYP2D6 activity. Coadministration of propafenone to extensive metabolizers decreased oral clearance of R-(-)-mexiletine (41 +/- 11 L/h to 28 +/- 7 L/h) and S-(+)-mexiletine (from 43 +/- 15 L/h to 29 +/- 11 L/h) to an extent such that these values were similar to those measured in poor metabolizers. Coadministration of propafenone to extensive metabolizers decreased by 71%, 67%, and 73% the partial metabolic clearances of mexiletine to hydroxymethylmexiletine, m-hydroxymexiletine, and p-hydroxymexiletine, respectively. Only the partial metabolic clearance of mexiletine to hydroxymethylmexiletine was significantly decreased by the administration of propafenone. Propafenone pharmacokinetic parameters were not changed during the concomitant administration of mexiletine. Significant changes in electrocardiographic parameters did not occur with the use of these two drugs in healthy volunteers. However, patients with underlying cardiac ischemic disease may be predisposed to proarrhythmia due to potentiation of drug effects 1.
Common questions
Can I take Mexiletine and Propafenone together?
An increased risk of mexiletine toxicity (cardiac arrhythmia) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Mexiletine and Propafenone interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Mexiletine or Propafenone need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (1)
- Labbe L, O'Hara G, Lefebvre M, et al: Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther 2000; 67:44-57.
Keep reading about Mexiletine
Keep reading about Propafenone
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