Mexiletine Drug Interactions: What to Avoid and What to Tell Your Doctor

Mexiletine interacts with a significant number of medications — over 90 documented drug interactions, according to prescribing information. Because mexiletine is used for life-threatening heart rhythm disorders, interactions that affect its blood levels or add to cardiac effects can be medically serious. This guide explains the most important mexiletine drug interactions in plain language.

Why Mexiletine Has So Many Drug Interactions

Mexiletine is primarily metabolized by two liver enzymes:

CYP1A2 and CYP2D6. Any drug that inhibits these enzymes will increase mexiletine blood levels (potentially causing toxicity), and any drug that induces these enzymes will decrease mexiletine levels (potentially causing treatment failure). Additionally, mexiletine itself inhibits CYP1A2, so it can increase blood levels of other medications that are broken down by that enzyme.

Contraindicated Drug Combinations (Do NOT Use Together)

These drugs should not be used together with mexiletine:

Pimozide (Orap): Mexiletine inhibits CYP1A2, dramatically raising pimozide levels and increasing the risk of dangerous QTc interval prolongation and potentially fatal arrhythmias.

Tizanidine (Zanaflex): Mexiletine significantly raises tizanidine blood levels via CYP1A2 inhibition, dramatically increasing the risk of excessive sedation, low blood pressure, and other serious side effects.

Duloxetine (Cymbalta): Mexiletine increases duloxetine exposure via CYP1A2 inhibition. This combination is contraindicated.

Dofetilide (Tikosyn): Additive cardiac effects between two antiarrhythmics create risk of fatal arrhythmia.

Alosetron (Lotronex): Mexiletine raises alosetron levels via CYP1A2 inhibition, increasing risk of serious gastrointestinal complications.

Drugs That Reduce Mexiletine's Effectiveness (Inducers)

These medications speed up mexiletine's metabolism, lowering its blood levels and potentially making it ineffective at controlling your arrhythmia:

Phenytoin (Dilantin): An anti-seizure drug that strongly induces CYP1A2 and CYP2D6, significantly lowering mexiletine plasma levels. If you take both, mexiletine level monitoring is strongly recommended.

Rifampin (Rifadin): A powerful CYP1A2 inducer used for tuberculosis; can dramatically lower mexiletine levels.

Phenobarbital: Another CYP1A2 inducer; decreases mexiletine effectiveness.

Drugs That Raise Mexiletine Levels (Inhibitors)

These drugs slow mexiletine's metabolism, causing it to build up in your system and potentially increasing side effects:

Quinidine: A CYP2D6 inhibitor that increases mexiletine levels. Use with caution; dose adjustment may be needed.

Fluoxetine (Prozac) and Paroxetine (Paxil): SSRIs that inhibit CYP2D6, potentially raising mexiletine levels and increasing the risk of side effects. Use with caution and monitor closely.

Fluvoxamine: A potent CYP1A2 inhibitor that can significantly increase mexiletine blood levels.

Cimetidine (Tagamet): An over-the-counter heartburn drug that can raise mexiletine levels. This is one of the most overlooked interactions — avoid cimetidine while taking mexiletine; use a different antacid instead.

Medications Mexiletine Can Affect

Because mexiletine inhibits CYP1A2, it raises blood levels of other drugs metabolized by that enzyme:

Theophylline: Used for asthma/COPD; mexiletine can raise theophylline levels significantly, increasing toxicity risk. Monitor theophylline levels carefully.

Caffeine: Mexiletine slows caffeine metabolism, so coffee and caffeinated beverages may have a stronger effect.

Melatonin: Mexiletine can raise melatonin levels; limit or avoid melatonin supplements while taking mexiletine.

What to Tell Your Doctor and Pharmacist

Before starting mexiletine, give your doctor and pharmacist a complete list of every medication you take — prescription, over-the-counter, supplements, and herbal products. Pay special attention to:

Any antiarrhythmics (amiodarone, lidocaine, flecainide, propafenone, quinidine)

Antidepressants (especially SSRIs like fluoxetine, paroxetine, fluvoxamine)

Anti-seizure medications (phenytoin, phenobarbital)

Antibiotics, especially rifampin

Any OTC heartburn drugs (avoid cimetidine/Tagamet specifically)

Theophylline or other asthma medications

Muscle relaxants (especially tizanidine — contraindicated)

See also our guides on mexiletine side effects and what mexiletine is used for for more patient-focused information.