Mexiletine is an oral antiarrhythmic agent that is used for suppression of ventricular arrhythmias. Long term mexiletine therapy is associated with a low rate of serum enzyme elevations and is a rare cause of clinically apparent acute liver injury.
Mexiletine (mex il' e teen) is an analogue of the local anesthetic lidocaine and has electrophysiological effects that resemble quinidine (antiarrhythmic Class IB). Mexiletine appears to act by blocking open sodium channels and outward potassium channels. As a consequence, it decreases cardiac automaticity, increases refractory periods and slows conduction. Mexiletine was approved for use in the United States in 1985, and current indications include suppression of life threatening ventricular arrhythmias including ventricular tachycardia. It is also effective in treating painful diabetic neuropathy. Mexiletine is available in capsules of 150, 200 and 250 mg generically and under the brand name Mexitil. The usual maintenance dose in adults is 200 to 300 mg every 6 hours. The dosage used to treat neuropathy is typically 300 mg daily. The most common side effects include dizziness, anxiety, gastrointestinal upset, nausea, blurred vision and skin rash.
In clinical trials, mexiletine was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations (~0.5%). Despite wide scale use, mexiletine has only rarely been linked to cases of clinically apparent liver injury. Most cases are associated with a hypersensitivity reaction. Patients have presented after 2 to 6 weeks of mexiletine therapy with a syndrome of fever, rash and systemic symptoms (DRESS syndrome), with eosinophilia or atypical lymphocytosis and liver test abnormalities. The pattern of serum enzyme elevations has been hepatocellular or mixed and the jaundice mild or absent. Autoimmune features were not present. Cases of Stevens Johnson syndrome have also been reported. Corticosteroids were often used, but largely for the fever and skin rash rather than the liver disease which was typically mild. Rare instances of cholestatic hepatitis with mexiletine therapy have also been reported and may represent a different form of liver injury.
Mechanism of Injury
The liver injury from mexiletine appears to be mediated by a hypersensitivity reaction. Mexiletine is metabolized in the liver by the cytochrome P450 system and an immunoallergic metabolite may be produced. The hypersensitivity reaction to mexiletine may be more common in Asian than other populations.
Outcome and Management
The liver injury due to mexiletine is usually overshadowed by the signs and symptoms of hypersensitivity. No cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome due to mexiletine have been reported. The signs and symptoms of hypersensitivity typically respond rapidly to corticosteroid therapy, but it is unclear whether the liver injury is similarly affected by the immunosuppression. There have been no reports of cross sensitivity to the liver injury between mexiletine and other oral antiarrhythmics, but shared sensitivity is unlikely.
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Case 1. Drug rash with eosinophilia and liver injury attributed to mexiletine.
[Modified from: Higa K, Hirata K, Dan K. Mexiletine-induced severe skin eruption, fever, eosinophilia, atypical lymphocytosis, and liver dysfunction. Pain 1997; 73: 97-9. PubMed Citation]
A 64 year old man developed rash and fever 30 days after starting mexiletine (100 mg three times daily) for a painful, postherpetic neuropathy. He had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. His other medications included amitriptyline (125 mg daily) and alprazolam (0.4 mg three times daily) which he had taken for the previous 2 years. On examination, the temperature was 38.3 oC. He had a morbilliform skin rash involving the face and trunk, but was not jaundiced. Laboratory tests showed a normal white count (7,300/μL) with 3% eosinophils and 1% atypical lymphocytes. Serum aminotransferase (ALT 252 U/L and AST 235 U/L) and alkaline phosphatase levels (574 U/L) were both elevated, but bilirubin was normal (0.7 mg/dL) (Table). His medications were stopped, but during the next week the rash worsened and he developed a marked eosinophilia (10.5%), atypical lymphocytosis (9.5%) and jaundice (Table). He was treated with dexamethasone (8 mg daily), followed by rapidly tapering doses of oral prednisolone. The fever and the rash improved, disappearing within 4 weeks. Jaundice also resolved rapidly, but serum alkaline phosphatase decreased more slowly and was still slightly elevated 7 weeks after stopping mexiletine. Amitriptyline was resumed at a higher dose without recurrence of jaundice or rash.
|Medication:|| Mexiletine (100 mg three times a day)|
|Pattern:|| Mixed-cholestatic (R=2.2, falling to 1.8)|
|| 3+ (jaundice, hospitalization)
|| 30 days to rash, 38 to jaundice
|Recovery:|| Incomplete at 6 weeks|
|Other medications:|| Amitriptyline, alprazolam|
|Days After Starting
||Days After Stopping
||Alk P (U/L)
|| Eosinophils 51%
|| Amitriptyline resumed
| Normal Values
The clinical presentation was typical of DRESS syndrome (drug rash with eosinophilia and systemic symptoms) such as occurs with the aromatic anticonvulsants and allopurinol. Rash is not an uncommon side effect of mexiletine, but liver injury and jaundice are rare. The cause is likely hypersensitivity and corticosteroids are often used with an immediate on fever and skin rash. Whether the liver injury is improved by corticosteroid therapy is unclear. In this publication, long term follow up information was not provided.
REPRESENTATIVE TRADE NAMES
Mexiletine – Generic, Mexitil®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 14 February 2014
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Campbell NP, Pantridge JF, Adgey AA. Long-term oral antiarrhythmic therapy with mexiletine. Br Heart J 1978; 40: 796-801. PubMed Citation (48 patients treated with mexiletine long term, found side effects were common but no mention of liver injury or ALT elevations).
Pernot C, Netter P, Marcon F, Weber JL. [Reversible hepatic anomalies during treatment with mexiletine]. Presse Med 1983; 12: 1938. French. PubMed Citation (48 year old man developed asymptomatic ALT elevations 15 days after starting mexiletine, but they decreased and drug was continued to 3 months when ALT rose to 1030 U/L, GGT 265 U/L, bilirubin 1.1 mg/dL, falling towards normal over next 4 months after stopping).
Geisler C, Keiding S. [Cholestatic hepatitis during treatment with mexiletine/lidocaine]. Ugeskr Laeger 1984; 146: 1212-3. Danish. PubMed Citation
Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet 1988 Jan; 1: 9-11. PubMed Citation (Cross over, double blind trial of 26 weeks of mexiletine for diabetic neuropathy; no mention of ALT levels).
Higa K, Hirata K, Dan K. Mexiletine-induced severe skin eruption, fever, eosinophilia, atypical lymphocytosis, and liver dysfunction. Pain 1997; 73: 97-9. PubMed Citation (64 year old man developed jaundice, fever and rash 30 days after starting mexiletine [bilirubin 3.7 mg/dL, ALT 242 U/L, Alk P 1280 U/L, 51% eosinophilia, 9% atypical lymphocytes], resolving with corticosteroid therapy in 4 weeks: Case 1).
Roden DM. Antiarrhythmic drugs: from mechanisms to clinical practice. Heart 2000; 84: 339-46. PubMed Citation (Overview of antiarrhythmic drugs which are separated in four classes based upon molecular target: I being sodium channel blockers; II beta blockers; III potassium channel blockers; and, IV calcium channel blockers; and, some agents having multiple targets).
Sasaki K, Yamamoto T, Kishi M, Yokozeki H, Nishioka K. Acute exanthematous pustular drug eruption induced by mexiletine. Eur J Dermatol 2001; 11: 469-71. PubMed Citation (56 year old man developed rash 1 month after starting mexiletine [ALT 129 U/L, bilirubin and Alk P not given, eosinophils 20%], resolving within 3 months of stopping).
Seino Y, Yamauchi M, Hirai C, Okumura A, Kondo K, Yamamoto M, Okazaki Y. A case of fulminant Type 1 diabetes associated with mexiletine hypersensitivity syndrome. Diabet Med 2004; 21: 1156-7. PubMed Citation (46 year old man developed rash 41 days after starting mexiletine for diabetic neuropathy [ALT 66 rising to ~720 U/L, bilirubin and Alk P not given], resolving with corticosteroid therapy with worsening of diabetes).
Sekiguchi A, Kashiwagi T, Ishida-Yamamoto A, Takahashi H, Hashimoto Y, Kimura H, Tohyama M, et al. Drug-induced hypersensitivity syndrome due to mexiletine associated with human herpes virus 6 and cytomegalovirus reactivation. J Dermatol 2005; 32: 278-81. PubMed Citation (66 year old man developed fever and rash with ALT elevations one month after starting mexiletine with progressive course, and HHV-6 and CMV present in serum, and death from myocarditis).
Yagami A, Yoshikawa T, Asano Y, Koie S, Shiohara T, Matsunaga K. Drug-induced hypersensitivity syndrome due to mexiletine hydrochloride associated with reactivation of human herpesvirus 7. Dermatology 2006; 213: 341-4. PubMed Citation (44 year old developed rash, fever and mononucleosis-like syndrome 6 months after starting mexiletine [ALT 144 U/L, atypical lymphocytes 15%, bilirubin and Alk P not given], with presence of human herpesvirus-7 DNA in white cells and skin; treated with prednisolone and resolved in 2-3 months).
Drugs for cardiac arrhythmias. Treat Guidel Med Lett 2007; 5: 51-8. PubMed Citation (Concise review of drugs for arrhythmias; mexiletine is an orally effective congener of lidocaine and is used as an alternative to amiodarone for ventricular arrhythmias; mentions hepatitis as an adverse event).
Lee SP, Kim SH, Kim TH, Sohn JW, Shin DH, Park SS, Yoon HJ. A case of mexiletine-induced hypersensitivity syndrome presenting as eosinophilic pneumonia. J Korean Med Sci 2010; 25: 148-51. PubMed Citation (82 year old man developed cough, fever and rash 6 months after starting mexiletine [ALT 321 U/L, bilirubin and Alk P not given, eosinophils 24%], eosinophilic pneumonitis on lung biopsy, resolving with prednisone therapy within 2 months of stopping).
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