Mexiletine is an oral, local anesthetic-type antiarrhythmic agent similar to lidocaine and tocainide. Mexiletine is a class Ib antiarrhythmic according to the Vaughan-Williams classification and is used to treat life-threatening ventricular arrhythmias. It also has been used successfully in the treatment of pain associated with diabetic neuropathy. Mexiletine was approved by the FDA in December 1985, and the patent expired in June 1994.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with food or antacids.
Gastrointestinal adverse events are among the most frequently reported with mexiletine. When compared to placebo, nausea, vomiting, and pyrosis (heartburn) were reported in 39.3% of patients (vs. 6.1% with placebo). In comparative trials (with quinadine, procainamide, and disopyramide), upper GI distress (unspecified, 41%), diarrhea (5.2%), constipation (4%), changes in appetite (2.6%), xerostomia (2.8%), and abdominal pain, cramps, and discomfort (1.2%), along with rare reports of changes in oral mucous membranes, salivary changes, dysphagia, peptic ulcer, upper GI bleeding, and esophageal ulceration, were reported. Dyspepsia was reported post-marketing. GI events are usually dose-related and are reversible when the dose is reduced. However, administration with food or an antacid will also help alleviate these effects.
Like other antiarrhythmics, mexiletine can worsen some arrhythmias (arrhythmia exacerbation). Increased ventricular arrhythmias are of particular concern for patients with sustained ventricular tachycardia. Mexiletine was studied in placebo-controlled and comparative (to quinadine, procainamide, and disopyramide) trials. In the placebo and comparison trials, both chest pain (unspecified) (7.5% vs. 4.1% in placebo trials; 2.6% in comparative trials), increased ventricular arrhythmia/premature ventricular contractions (PVCs) (1.9% vs. 0 in placebo trials; 1% in comparative trials), and palpitations (7.5% vs. 10.2% in placebo trials; 4.3% in comparative trials) were reported. In the comparative trials there were reports of angina or angina-like pain (1.7%). Less than 1% of patients in the comparative trial reported syncope, edema, hot flashes, hypertension, diaphoresis, and congestive heart failure, and there were rare reports of hypotension, bradycardia, AV block/conduction disturbances, atrial arrhythmias, and cardiogenic shock. Exacerbation of congestive heart failure in patients with preexisting compromised ventricular function was also reported post-marketing.
Nervous system adverse events are among the most frequently reported with mexiletine, some of which are related to or result in musculoskeletal and psychological effects. The most frequently reported include lightheadedness or dizziness (10.5%), tremor (12.6%), and coordination difficulties or ataxia (10.2%). Mexiletine was studied in placebo-controlled and comparative (to quinadine, procainamide, and disopyramide) trials. In the placebo and comparison trials, nervousness (11.3% vs. 6.1% in placebo trials; 5% in comparative trials), paresthesias (3.8% vs. 2% in placebo trials; 2.4% in comparative trials), changes in sleep habits (7.5% vs. 16.3% in placebo trials; 7.1% in comparative trials), weakness (1.9% vs. 4.1% in placebo trials; 5% in comparative trials), fatigue (1.9% vs. 2% in placebo trials; 3.8% in comparative trials), confusion (1.9% vs. 2% in placebo trials; 2.6% in comparative trials), and headache (7.5% vs. 6.1% in placebo trials; 5.7% in comparative trials) were reported. In the comparative trials there were reports of speech difficulties (2.6%), depression (2.4%), and arthralgia (1.7%). Less than 1% of patients in the comparative trial reported short-term memory impairment, loss of consciousness, other psychological changes, and malaise, and there were rare reports of hallucinations and other psychological changes, psychosis, and seizures. Drowsiness was reported post-marketing.
Although less than 1% of patients treated with mexiletine presented with blood dyscrasias, there have been reports of agranulocytosis or marked leukopenia (0.06%), mild leukopenia (0.08%), and thrombocytopenia (0.15%). In addition, two patients experienced myelofibrosis; one patient was receiving long-term thiotepa therapy and the other had pre-treatment myeloid abnormalities. The causal relationship is questionable because many of these patients were seriously ill and receiving other medications with known hematologic effects. If drug-related hematologic abnormalities occur, mexiletine should be discontinued. Blood counts usually return to normal within one month of drug discontinuation.
Skin and dermatologic adverse events have been reported. Mexiletine was studied in placebo-controlled and comparative (to quinadine, procainamide, and disopyramide) trials where rash (unspecified) (3.8% vs. 2% in placebo trials; 4.2% in comparative trials) was reported. There were rare cases of exfoliative dermatitis, Stevens-Johnson syndrome, hair loss, xerosis, and hypersensitivity reactions in the comparative trials.
Otologic, ophthalmic, and respiratory adverse events have been reported. Mexiletine was studied in placebo-controlled and comparative (to quinidine, procainamide, and disopyramide) trials where tinnitus (1.9% vs. 4.1% in placebo trials; 2.4% in comparative trials), blurred vision (7.5% vs. 2% in placebo trials; 5.7% in comparative trials), and dyspnea (5.7% vs. 10.2% in placebo trials; 3.3% in comparative trials) were reported. In the comparative trials there were reports of fever (1.2%). Less than 1% of patients in the comparative trial reported pharyngitis, and there were rare reports of hiccups and laryngeal and pharyngeal changes. In post-marketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of nystagmus.
Mexiletine was studied in placebo-controlled and comparative (to quinidine, procainamide, and disopyramide) trials. In the comparative trial, less than 1% of patients reported abnormal liver function tests, urinary retention or hesitancy, impotence (erectile dysfunction), and libido decrease, and there were rare reports of pancreatitis.
Mexiletine was studied in placebo-controlled and comparative (to quinadine, procainamide, and disopyramide) trials. In the comparative trial, < 1% of patients reported SLE syndrome or lupus-like symptoms.
In 3-month controlled trials, elevations of SGOT 3 times the upper limit of normal or more occurred in about 1% of both mexiletine-treated and control patients. About 2% of patients in the mexiletine compassionate use program experienced SGOT elevations 3 times the upper limit of normal or more. These elevated hepatic enzymes frequently occurred in association with congestive heart failure, myocardial infarction, blood transfusions, and other medications. These elevations were often transient and asymptomatic, usually not associated with elevated bilirubin concentrations, and usually did not require discontinuation of mexiletine therapy. Marked elevations of SGOT (more than 1,000 Units/L) were seen before death in 4 patients with end-stage cardiac disease. Rare instances of hepatotoxicity, including severe hepatitis or hepatic necrosis, have been reported with mexiletine therapy. Carefully evaluate all patients with an abnormal liver test or signs or symptoms of hepatic dysfunction. If persistent or worsening of elevation of hepatic enzymes occurs, consider discontinuing mexiletine.
Mexiletine is contraindicated in patients with preexisting second- or third-degree AV block, unless an artificial pacemaker is in place. Mexiletine can increase the risk of arrhythmias or complete heart block in patients with sinus bradycardia or incomplete heart block and should be used with caution in these patients. Mexiletine also is contraindicated in patients in cardiogenic shock.
Mexiletine should be used with extreme caution in patients with hypotension because the drug can worsen this condition. Mexiletine increases the risk for further blood pressure reductions.
Like other antiarrhythmics, mexiletine is proarrhythmic and can worsen or induce cardiac arrhythmias. Increased ventricular arrhythmias are of particular concern for patients with familial history of QT prolongation, familial long QT syndrome, sustained ventricular tachycardia or similar cardiac heart rhythm abnormalities. Other patients at risk for proarrhythmic effects include patients with a history of myocardial infarction or acute myocardial infarction. In the CAST trial, a randomized double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias, has demonstrated an excessive rate of mortality or non-fatal cardiac arrest in patients treated with encainide or flecainide (7.7%) compared to placebo (3%). The enrolled patients had a history of myocardial infarction (more than 6 days but less than 2 years); the average duration of antiarrhythmic therapy was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmics is uncertain. Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for antiarrhythmic drugs in patients without life-threatening arrhythmias, the use of mexiletine should be reserved for patients with life-threatening ventricular arrhythmias. Mexiletine should be used with caution in older adult patients, such as geriatric adults with potential or undiagnosed heart disease, and also in patients with severe congestive heart failure because of the potential to aggravating this condition; exacerbation of congestive heart failure may occur in some patients with pre-existing ventricular dysfunction. Mexiletine should also be used with caution in patients with congestive heart failure, acute myocardial infarction, or hepatic disease. These conditions may reduce hepatic blood flow, therefore reduce hepatic metabolism, resulting in prolongation of effect. Cirrhosis markedly impairs the elimination of mexiletine; therefore, dosage should be reduced in patients with hepatic impairment with close monitoring for therapeutic effectiveness and safety. Rare instances of hepatotoxicity, including hepatic necrosis, have occurred in association with mexiletine treatment. In postmarketing experience, abnormal liver function tests have been reported, some in the first few weeks of mexiletine therapy. Most of these have been observed in the setting of congestive heart failure or ischemia although the relationship to mexiletine has not been established.
Severe renal disease, renal failure, or renal impairment has been shown to prolong the half-life of mexiletine. Dosage reduction may be needed in patients with CrCl <= 10 ml/min (see Dosage).
Mexiletine should be used with caution with pre-existing seizure disorder. It can precipitate seizure activity in these patients. Mexiletine is associated with a relatively high incidence of tremor (> 10%), which could exacerbate pre-existing Parkinson's disease.
Although less than 1% of patients treated with mexiletine presented with blood dyscrasias and the causal relationship is unknown due to coexisting factors, there have been reports of agranulocytosis or marked leukopenia (0.06%), mild leukopenia (0.08%), and thrombocytopenia (0.15%). If drug-related hematologic abnormalities occur, mexiletine should be discontinued.
There are no adequate and well-controlled studies to assess the safety of mexiletine use in pregnant women. In reproduction studies involving rats, mice, and rabbits, an increase in fetal absorption was observed at doses up to 4 times the maximum human oral dose; there was no evidence of teratogenicity or impaired fertility. The safe use of mexiletine during pregnancy has not been established. Mexiletine should not be used during pregnancy unless the potential benefits to the mother outweigh the potential risks to the fetus.
According to the manufacturer, mexiletine is excreted into breast milk in concentrations similar to those in human plasma. The manufacturer recommends that if mexiletine therapy is essential to the mother, an alternative to breast-feeding should be considered. In a case report involving a 30-year old woman who received mexiletine 200 mg three times daily during both pregnancy and the postpartum period, breast milk and infant blood samples were obtained on postpartum days 2 and 5 and the reported mean milk: plasma ratio was 1.45 (range, 0.78 to 1.89). A 17-day old, breast-feeding infant was reported to have suboptimal growth and failure to feed; the infant's mother received mexiletine 250 mg three times daily during pregnancy and breast-feeding. Breast-feeding was discontinued and the infant regained weight and attained an acceptable growth curve. In previous American Academy of Pediatrics (AAP) recommendations, mexiletine use was considered as usually compatible with breast-feeding ; however, there are relatively little data available. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Tobacco smoking has been noted to significantly enhance the elimination rate of mexiletine. Conversely, because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of mexiletine, despite the initiation of nicotine replacement. Monitor patients carefully for the desired clinical effects when changes in tobacco smoking status occur.
Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported with mexiletine therapy. DRESS may resemble an acute viral infection and may present as a serious rash, eosinophilia, fever, and lymphadenopathy in association with organ involvement (i.e., hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis). If DRESS is suspected, discontinue mexiletine therapy.
For the treatment of life threatening ventricular arrhythmias such as ventricular tachycardia:
Oral dosage:
Adults: Initially, 200 mg PO every 8 hours (may load with 400 mg PO, if needed). Patients with significant right-sided heart failure may require reduced dosage due to hepatic congestion (see dosage for patients with hepatic impairment). Dosage may be increased by 50-100 mg at intervals >= 2-3 days if needed. The usual dosage is 200-300 mg PO every 8 hours. If an adequate response has not been achieved at 300 mg PO every 8 hours and there are no intolerable side effects, a dose of 400 mg PO every 8 hours may be tried. Maximum dosage is 1200 mg/day. In some patients, a 12-hour dosage schedule may be used to improve compliance. If adequate suppression is achieved with a dose of 300 mg PO or less every 8 hours, the same total daily dose may be given in divided doses every 12 hours with careful monitoring of the degree of suppression of ventricular ectopy. This dose may be adjusted to a maximum of 450 mg PO every 12 hours. NOTE: When transferring to mexiletine from other class I antiarrhythmic agents, administer the initial 200 mg dose of mexiletine as follows: 6-12 hours following the last dose of quinidine sulfate, 6-12 hours following the last dose of disopyramide, 8-12 hours following the last dose of tocainide, or 3-6 hours after the last dose of procainamide.
Elderly: See adult dosage. No dosage adjustment is necessary. Mexiletine clearance decreases slightly and linearly with aging; however, clinical efficacy and safety are similar in elderly and younger patients.
Adolescents: See dosage for adults or children, depending on the patient age, weight, and stature. Maximum dosage is 1200 mg/day PO or 15 mg/kg/day PO, whichever is less.
Children: Doses of 1.4-5 mg/kg PO (mean 3.3 mg/kg), given every 8 hours, have been used. Start with a low dose and titrate to desired effect and serum concentrations.
For the treatment of neuropathic pain* syndromes:
-for the treatment of neuropathic pain*:
Oral dosage:
Adults: A dosage of 450-600 mg/day PO has been suggested.
Elderly: See adult dosage. No dosage adjustment is necessary. Mexiletine clearance decreases slightly and linearly with aging; however, clinical efficacy and safety are similar in elderly and younger patients.
-for the treatment of pain associated with diabetic neuropathy*:
Oral dosage:
Adults: Success was demonstrated in a small number of patients with multiple symptoms. They were given 75 mg PO three times daily, increased weekly if needed to 150-225 mg PO three times daily.
Elderly: See adult dosage. No dosage adjustment is necessary. Mexiletine clearance decreases slightly and linearly with aging; however, clinical efficacy and safety are similar in elderly and younger patients.
Maximum Dosage Limits:
-Adults
1200 mg/day PO.
-Elderly
1200 mg/day PO.
-Adolescents
1200 mg/day PO or 15 mg/kg/day PO, whichever is less.
-Children
15 mg/kg/day PO.
Patients with Hepatic Impairment Dosing
Reduce dosage in patients with hepatic impairment by about one-fourth or one-third of the usual dosage; monitor closely for therapeutic effectiveness and safety.
Patients with Renal Impairment Dosing
CrCl > 10 ml/min: no dosage adjustment needed.
CrCl <= 10 ml/min: administer 50-75% of usual dosage.
Intermittent hemodialysis
No dosage adjustment is needed.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Acetaminophen; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Acetazolamide: (Major) If acidifying or alkalinizing agents, such as carbonic anhydrase inhibitors, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Acyclovir: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with acyclovir. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and acyclovir is a weak CYP1A2 inhibitor.
Adagrasib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with adagrasib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Allopurinol: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with allopurinol. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
Alosetron: (Major) Concomitant use of alosetron with mexiletine should be avoided due to the risk for increased alosetron serum concentrations and serious adverse reactions. Alosetron is metabolized by CYP1A2; mexiletine is a moderate inhibitor of this enzyme.
Amiodarone: (Major) Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2. Amiodarone inhibits both of these enzymes. However, one study showed no effect of amiodarone on mexiletine clearance in patients with supraventricular arrhythmias.
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for mexiletine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of mexiletine. Celecoxib is a CYP2D6 inhibitor, and mexiletine is a CYP2D6 substrate.
Amobarbital: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Anagrelide: (Moderate) Anagrelide is partially metabolized by and inhibits CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as mexiletine, patients should be monitored for increased adverse effects of either drug.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and mexiletine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased mexiletine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Articaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Ascorbic Acid, Vitamin C: (Minor) Ascorbic acid, vitamin C in doses greater than 2 grams per day can lower urinary pH, potentially causing enhanced the plasma clearance of mexiletine.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine. (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Aspirin, ASA; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) If alkalinizing agents, such as sodium bicarbonate, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Atazanavir; Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Barbiturates: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Bendamustine: (Major) Consider the use of an alternative therapy if mexiletine treatment is needed in patients receiving bendamustine. Mexiletine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and mexiletine is a CYP1A2 inhibitor.
Berotralstat: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with berotralstat. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Bupivacaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Bupivacaine; Lidocaine: (Major) Mexiletine is chemically and pharmacologically similar to lidocaine; cardiac and toxic effects may be additive. In addition, concurrent use may increase plasma lidocaine concentrations due to the displacement of lidocaine from tissue binding sites by mexiletine. If used together, monitor lidocaine plasma concentrations and adjust the dosage as required.
Bupropion: (Major) Coadministration of bupropion and mexiletine can increase the exposure of mexiletine. If used together, it may be necessary to decrease the dose of mexiletine and slowly titrate to effect. Mexiletine is primarily metabolized via CYP2D6 and bupropion and its metabolites are inhibitors of CYP2D6.
Bupropion; Naltrexone: (Major) Coadministration of bupropion and mexiletine can increase the exposure of mexiletine. If used together, it may be necessary to decrease the dose of mexiletine and slowly titrate to effect. Mexiletine is primarily metabolized via CYP2D6 and bupropion and its metabolites are inhibitors of CYP2D6.
Butalbital; Acetaminophen: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Butalbital; Acetaminophen; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine. (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine. (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine. (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Caffeine; Sodium Benzoate: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Cannabidiol: (Moderate) Consider a dose reduction of mexiletine as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased mexiletine exposure is possible. Mexiletine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor. The clearance of mexiletine was decreased by 38% after the administration of another CYP1A2 inhibitor.
Capivasertib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with capivasertib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and capivasertib is a moderate CYP2D6 inhibitor.
Capmatinib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with capmatinib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and capmatinib is a moderate CYP1A2 inhibitor.
Carbamazepine: (Moderate) Carbamazepine induces the hepatic metabolism of other drugs, and should be used cautiously with mexiletine. Conversely, mexiletine doses may need to be reduced if a hepatic enzyme inducer is stopped while mexiletine therapy continues.
Carbonic anhydrase inhibitors: (Major) If acidifying or alkalinizing agents, such as carbonic anhydrase inhibitors, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Celecoxib: (Moderate) A dosage adjustment may be warranted for mexiletine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of mexiletine. Celecoxib is a CYP2D6 inhibitor, and mexiletine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) A dosage adjustment may be warranted for mexiletine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of mexiletine. Celecoxib is a CYP2D6 inhibitor, and mexiletine is a CYP2D6 substrate.
Chlorpromazine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as chlorpromazine, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Cimetidine: (Moderate) Cimetidine exerts variable effects on the serum levels of mexiletine, so patients should be monitored closely during concomitant therapy with these two agents.
Cinacalcet: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with cinacalcet. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Ciprofloxacin: (Moderate) Mexiletine is partially metabolized by CYP1A2 isoenzymes. Although more data are needed, ciprofloxacin appears to decrease the hepatic clearance of mexiletine to a modest degree. The mechanism of this interaction may be ciprofloxacin inhibition of CYP1A2. Clinicians should be aware of the potential for mexiletine related adverse reactions.
Citalopram: (Moderate) Citalopram mildly inhibits the hepatic CYP2D6 isoenzyme at therapeutic doses. This can result in increased concentrations of drugs metabolized via the same pathway, including mexiletine.
Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as mexiletine, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for mexiletine-related adverse reactions.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with mexiletine and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Mexiletine is a moderate CYP1A2 inhibitor.
Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of mexiletine if coadministered. To minimize potential for interactions, consider administering oral antiarrhythmics such as mexiletine at least 1 hour before or at least 4 hours after colesevelam.
Dacomitinib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with dacomitinib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
Darifenacin: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with darifenacin. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor.
Darunavir: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with darunavir. Concurrent use may result in elevated mexiletine plasma concentration. Mexiletine is a substrate for CYP2D6; darunavir is an inhibitor of this enzyme.
Darunavir; Cobicistat: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with darunavir. Concurrent use may result in elevated mexiletine plasma concentration. Mexiletine is a substrate for CYP2D6; darunavir is an inhibitor of this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with darunavir. Concurrent use may result in elevated mexiletine plasma concentration. Mexiletine is a substrate for CYP2D6; darunavir is an inhibitor of this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Delavirdine: (Major) Because mexiletine is metabolized by CYP2D6, delavirdine which is a potent inhibitor of cytochrome P450 2D6, might decrease the metabolism of mexiletine. Clinicians should be aware of the potential for severe adverse reactions.
Desvenlafaxine: (Major) Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as mexiletine, be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Dextromethorphan; Bupropion: (Major) Coadministration of bupropion and mexiletine can increase the exposure of mexiletine. If used together, it may be necessary to decrease the dose of mexiletine and slowly titrate to effect. Mexiletine is primarily metabolized via CYP2D6 and bupropion and its metabolites are inhibitors of CYP2D6.
Dextromethorphan; Quinidine: (Moderate) Quinidine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering quinidine with other CYP2D6 substrates, such as mexiletine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Dofetilide: (Contraindicated) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Before switching from another antiarrhythmic drug to dofetilide therapy, antiarrhythmics generally should be withheld for at least three half-lives prior to initiating dofetilide. According to the manufacturer, Class I (disopyramide, encainide, flecainide, lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, and tocainide) antiarrhythmic agents are associated with QT prolongation and ventricular arrhythmias and concurrent exposure with dofetilide could increase the risk of dofetilide-induced proarrhythmias.
Eliglustat: (Major) Coadministration of mexiletine and eliglustat may result in increased concentrations of mexiletine, which has a narrow therapeutic index; use these drugs together with extreme caution. If coadministration is necessary, titrate the mexiletine dose slowly to the desired clinical effect and monitor patients closely for mexiletine-related adverse effects such as cardiac arrhythmias. Mexiletine is a CYP2D6 substrate, and eliglustat is a CYP2D6 inhibitor.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inhibitors of CYP1A2, such as mexiletine, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Enasidenib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with enasidenib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 and CYP2D6 substrate and enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor. Coadministration with another strong CYP1A2 inhibitor decreased the clearance of mexiletine by 38%.
Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Ergotamine; Caffeine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Escitalopram: (Moderate) Caution is recommended during the coadministration of escitalopram with drugs metabolized by CYP2D6, such as mexiletine. Limited in vivo data suggest a modest inhibitory effect of CYP2D6 by escitalopram, which may result in increased concentrations of CYP2D6 substrates.
Ethotoin: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Etravirine: (Major) Mexiletine concentrations may be decreased when coadministered with etravirine. Coadminister these drugs with caution and monitor mexiletine concentrations when possible.
Everolimus: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with everolimus. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and everolimus is a weak CYP2D6 inhibitor.
Fedratinib: (Moderate) Monitor for an increase in mexiletine-related adverse reactions if coadministration with fedratinib is necessary. Mexiletine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor. In a drug interaction study, coadministration of another moderate CYP2D6 inhibitor did not alter the kinetics of mexiletine in CYP2D6 poor metabolizers. However, in extensive metabolizers, the metabolic clearance of mexiletine decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.
Fexinidazole: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with fexinidazole. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and fexinidazole is a moderate CYP1A2 inhibitor.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and mexiletine is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; mexiletine is a moderate CYP1A2 inhibitor. Concomitant use increased fezolinetant overall exposure by 360%.
Fluoxetine: (Moderate) Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including mexiletine. Increased plasma concentrations may increase the risk of proarrhythmias.
Fluvoxamine: (Major) Fluvoxamine appears to decrease the hepatic clearance of mexiletine. The mechanism of this interaction is most likely due to fluvoxamine inhibition of the CYP1A2 isoenzyme and a resultant 38% reduction in the clearance of mexiletine. If fluvoxamine and mexiletine are co-administered, serum mexiletine levels should be monitored and the patient closely observed.
Food: (Major) Advise patients to avoid cannabis use during mexiletine treatment due to decreased exposure of mexiletine which may alter its efficacy. Cannabis use induces CYP1A2 and mexiletine is a CYP1A2 substrate. The induction potential of cannabis is greatest with chronic inhalation. Other routes of administration or sporadic use may have less of an effect.
Fosphenytoin: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of ginger, Zingiber officinale. It is theoretically possible that ginger could affect the action of antiarrhythmics, however, no clinical data are available.
Green Tea: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, which could potentially reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine including caffeine from green tea.
Haloperidol: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as haloperidol, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Hydantoins: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Imatinib: (Major) Because mexiletine is metabolized by CPY 2D6, imatinib, STI-571, a potent inhibitor of cytochrome P450 2D6, might decrease the metabolism of mexiletine. Clinicians should be aware of the potential for severe adverse reactions.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class IB antiarrhythmics, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamotrigine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Leniolisib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with leniolisib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and leniolisib is a weak CYP1A2 inhibitor.
Lidocaine: (Major) Mexiletine is chemically and pharmacologically similar to lidocaine; cardiac and toxic effects may be additive. In addition, concurrent use may increase plasma lidocaine concentrations due to the displacement of lidocaine from tissue binding sites by mexiletine. If used together, monitor lidocaine plasma concentrations and adjust the dosage as required.
Lidocaine; Epinephrine: (Major) Mexiletine is chemically and pharmacologically similar to lidocaine; cardiac and toxic effects may be additive. In addition, concurrent use may increase plasma lidocaine concentrations due to the displacement of lidocaine from tissue binding sites by mexiletine. If used together, monitor lidocaine plasma concentrations and adjust the dosage as required. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Lidocaine; Prilocaine: (Major) Mexiletine is chemically and pharmacologically similar to lidocaine; cardiac and toxic effects may be additive. In addition, concurrent use may increase plasma lidocaine concentrations due to the displacement of lidocaine from tissue binding sites by mexiletine. If used together, monitor lidocaine plasma concentrations and adjust the dosage as required.
Lopinavir; Ritonavir: (Major) Ritonavir is an inhibitor of CYP3A4 and CYP2D6 (in vitro), and may increase exposure to drugs metabolized by these enzymes, such as mexiletine. Increased mexiletine serum concentrations may increase the risk for adverse reactions.
Melatonin: (Moderate) CYP1A2 inhibitors such as mexiletine may increase melatonin exposure. Melatonin is primarily metabolized by CYP1A2, with lesser contributions by CYP1A1, CYP2C9 and CYP2C19.
Meropenem: (Moderate) Monitor for decreased efficacy of mexiletine if coadministered with meropenem. Coadministration may decrease serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and meropenem is a CYP1A2 inducer.
Meropenem; Vaborbactam: (Moderate) Monitor for decreased efficacy of mexiletine if coadministered with meropenem. Coadministration may decrease serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and meropenem is a CYP1A2 inducer.
Methazolamide: (Major) If acidifying or alkalinizing agents, such as carbonic anhydrase inhibitors, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Methohexital: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as mexiletine may be increased when co-administered with mirabegron. Mexiletine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and mexiletine and consider an alternative COVID-19 therapy. Coadministration may increase mexiletine exposure resulting in increased toxicity. Mexiletine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Ritonavir is an inhibitor of CYP3A4 and CYP2D6 (in vitro), and may increase exposure to drugs metabolized by these enzymes, such as mexiletine. Increased mexiletine serum concentrations may increase the risk for adverse reactions.
Obeticholic Acid: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with obeticholic acid. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and obeticholic acid is a weak CYP1A2 inhibitor.
Olanzapine: (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
Olanzapine; Fluoxetine: (Moderate) Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including mexiletine. Increased plasma concentrations may increase the risk of proarrhythmias. (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
Olanzapine; Samidorphan: (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
Omeprazole; Sodium Bicarbonate: (Major) If alkalinizing agents, such as sodium bicarbonate, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Oritavancin: (Moderate) Mexiletine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of mexiletine may be reduced if these drugs are administered concurrently.
Osilodrostat: (Moderate) Monitor for an increase in mexiletine-related adverse reactions if coadministration with osilodrostat is necessary. Concurrent use may increase mexiletine exposure. Mexiletine is a CYP1A2 and CYP2D6 substrate; osilodrostat is a moderate CYP1A2 inhibitor and weak CYP3A4 inhibitor.
Pacritinib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with pacritinib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and pacritinib is a weak CYP1A2 inhibitor.
Panobinostat: (Major) The co-administration of panobinostat with mexiletine is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of mexiletine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and mexiletine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Moderate) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving mexiletine since this antiarrhythmic is metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of drugs metabolized via the same pathway, including mexiletine, which may increase the risk of side effects or proarrhythmia.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to mexiletine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while mexiletine is a CYP2D6 substrate.
Pentobarbital: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Perphenazine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as perphenazine, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Perphenazine; Amitriptyline: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as perphenazine, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Phenobarbital: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Phenytoin: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Pimozide: (Major) Concurrent use of pimozide with CYP1A2 inhibitors such as mexiletine should be avoided if possible. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
Pirfenidone: (Major) Avoid concomitant administration of mexilitine and pirfenidone because it may increase exposure to pirfenidone. If concurrent use cannot be avoided, closely monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Dosage redution, interruption of therapy, or discontinuation may be necessary. Mexiletine is a moderate inhibitor of CYP1A2, and pirfenidone is primarily metabolized by CYP1A2.
Pomalidomide: (Moderate) Use pomalidomide and mexiletine together with caution; increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If these drugs are used together, monitor for pomalidomide adverse events; a pomalidomide dose adjustment may be necessary. Pomalidomide is a CYP1A2 substrate and mexiletine is a moderate CYP1A2 inhibitor. In healthy volunteers, the plasma levels of a sensitive CYP1A2 substrate increased by 72% (range 35% to 136%) when mexiletine was co-administered with a sensitive CYP1A2 substrate.
Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Primidone: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Propafenone: (Moderate) The concomitant use of mexiletine with other antiarrhythmics can lead to additive pharmacodynamic, electrophysiologic, and/or toxic effects of the drug combination compared with either agent alone.
Propranolol: (Moderate) Mexiletine has been found to increase propranolol concentrations in patients receiving concomitant therapy. The significance of the elevated propranolol concentration is not known as beta-blockers have a wide therapeutic range. It may be prudent to monitor patients for adverse effects when mexiletine are combined with propranolol.
Quinidine: (Moderate) Quinidine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering quinidine with other CYP2D6 substrates, such as mexiletine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Quinine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as quinine, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Ramelteon: (Major) Coadministration of ramelteon with inhibitors of CYP1A2, such as mexiletine, may lead to increases in the serum concentrations of ramelteon.
Ranolazine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. Moderate CYP2D6 inhibitors, like ranolazine, could impair mexiletine metabolism and increase mexiletine concentrations and the risk for mexiletine-related side effects. Monitor for changes in heart rate and rhythm, as well as gastrointestinal and neurologic tolerance.
Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with mexiletine. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; mexiletine is a moderate CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Riluzole: (Moderate) Coadministration of riluzole with mexiletine may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and mexiletine is a CYP1A2 inhibitor.
Ritlecitinib: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with ritlecitinib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and ritlecitinib is a moderate CYP1A2 inhibitor.
Ritonavir: (Major) Ritonavir is an inhibitor of CYP3A4 and CYP2D6 (in vitro), and may increase exposure to drugs metabolized by these enzymes, such as mexiletine. Increased mexiletine serum concentrations may increase the risk for adverse reactions.
Rolapitant: (Major) Use caution if mexiletine and rolapitant are used concurrently, and monitor for mexiletine-related adverse effects and toxicities. Mexiletine is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Ropinirole: (Moderate) Ropinirole and mexiletine are both substrates and inhibitors of CYP1A2. Coadministration may result in increased serum concentrations of either agent.
Secobarbital: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Sertraline: (Moderate) Some SSRIs may interact with certain antiarrhythmics. Sertraline is a mild to moderate inhibitor of CYP2D6. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including encainide and mexiletine. Clinical data are not always available to document interactions. Increased plasma concentrations may increase the risk of proarrhythmia.
Sodium Bicarbonate: (Major) If alkalinizing agents, such as sodium bicarbonate, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for decreased efficacy of mexiletine if coadministered with taurursodiol. Coadministration may decrease serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and taurursodiol is a CYP1A2 inducer.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and mexiletine. Because tasimelteon is partially metabolized via CYP1A2, use with CYP1A2 inhibitors, such as mexiletine, may increase exposure to tasimelteon and the potential for adverse reactions.
Terbinafine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, including terbinafine, could theoretically impair mexiletine metabolism.
Teriflunomide: (Moderate) As teriflunomide is a weak inducer of CYP1A2, exposure to mexiletine, a CYP1A2 substrate, may be reduced. Caution should be exercised with concurrent use. Patients should be monitored for loss of antiarrhythmic effect if teriflunomide therapy is initiated. Conversely, mexiletine doses may need adjustment if teriflunomide treatment is discontinued.
Theophylline, Aminophylline: (Moderate) Mexiletine has been shown to decrease theophylline clearance, increase theophylline concentrations, and produce theophylline toxicity. Lower doses of theophylline should be used in patients receiving mexiletine or when mexiletine is added.
Thioridazine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as thioridazine, could theoretically impair mexiletine metabolism; the clinical significance of such interactions is unknown.
Tizanidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as mexiletine, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
Tobacco: (Major) Advise patients to avoid tobacco products while receiving mexiletine. Tobacco smoking has been noted to significantly enhance the rate of elimination of mexiletine, possibly leading to subtherapeutic clinical effects. Mexiletine is a CYP1A2 substrate and smoking tobacco induces CYP1A2.
Vemurafenib: (Major) Concomitant use of vemurafenib and mexiletine may result in increased mexiletine concentrations. Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2, while vemurafenib is a CYP1A2 inhibitor and a weak CYP2D6 inhibitor. Monitor patients for toxicity. Caution is recommended when administering CYP2D6 inhibitors with mexiletine, which has a narrow therapeutic index.
Viloxazine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with viloxazine. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with mexiletine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Mexiletine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zileuton: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with zileuton. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and zileuton is a weak CYP1A2 inhibitor.
Mexiletine inhibits the fast sodium channels of the myocardial cell membrane, decreasing the rate of rise and amplitude of the action potential, which increases the recovery period following repolarization. The drug decreases automaticity (increases the excitability threshold) in the His-Purkinje system, but it does not affect conduction velocity. Mexiletine decreases both the effective refractory period and the action potential duration of the His-Purkinje system. The effective refractory period is decreased less than the action potential duration, so the myocardium remains refractory even after the resting membrane potential has been restored. In summary, its antiarrhythmic effect may be related to the ability of the drug to increase the ratio of the effective refractory period to the action potential duration.
Mexiletine is administered orally. It is 50-60% protein-bound and is distributed into breast milk. Mexiletine is metabolized in the liver primarily to inactive metabolites (85%), although a minority of the metabolites are pharmacologically active. Elimination is primarily via biliary routes, with approximately 10% of the drug excreted unchanged in the urine. The plasma half-life is 10-12 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP1A2
Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2. Mexiletine is an inhibitor of CYP1A2 isoenzymes.
-Route-Specific Pharmacokinetics
Oral Route
Mexiletine is well absorbed following oral administration and, unlike lidocaine, does not undergo substantial first-pass metabolism. Oral bioavailability is approximately 90%.
-Special Populations
Hepatic Impairment
The half-life of mexiletine is prolonged significantly to an average of 25 hours in patients with hepatic failure.
Renal Impairment
Although the renal elimination of the drug is limited, urinary acidification will increase the rate of excretion, and severe renal dysfunction (CrCl < 10 ml/min) prolongs the mexiletine half-life to about 15.6 hours.
Geriatric
Mexiletine clearance decreases slightly and linearly with aging; however, dosage adjustment is considered unnecessary in elderly patients.
Other
The half-life of mexiletine is prolonged significantly to an average of 25 hours in patients with myocardial infarction or congestive heart failure.