Mexiletine Hydrochloride

• WARNINGS Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%).
• The average duration of treatment with encainide or flecainide in this study was ten months.
• The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain.
• Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of mexiletine as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmia.
• Acute Liver Injury In postmarketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with mexiletine hydrochloride.
• Most of these have been observed in the setting of congestive heart failure or ischemia and their relationship to mexiletine hydrochloride has not been established.

Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or preexisting second- or third-degree AV block (if no pacemaker is present).

• BOXED WARNING WARNINGS Mortality In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%).
• Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS) Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking mexiletine.
• DRESS typically presents with eosinophilia, fever, rash, and/or lymphadenopathy in association with other organ involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
• Discontinue mexiletine if DRESS is suspected.
• General If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored.
• A limited number of patients (45 of 475 in controlled clinical trials) with preexisting first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block.
• Caution should be exercised when it is used in such patients or in patients with preexisting sinus node dysfunction or intraventricular conduction abnormalities.
• Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias.
• This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia:
• see ADVERSE REACTIONS ), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia.
• In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.
• Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.
• Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine.
• The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.
• Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy.
• The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.
• SGOT Elevation and Liver Injury In three month controlled trials, elevations of SGOT greater than three times the upper limit of normal occurred in about 1% of both mexiletine-treated and control patients.
• Approximately 2% of patients in the mexiletine compassionate use program had elevations of SGOT greater than or equal to three times the upper limit of normal.
• These elevations frequently occurred in association with identifiable clinical events and therapeutic measures such as congestive heart failure, acute myocardial infarction, blood transfusions and other medications.
• These elevations were often asymptomatic and transient, usually not associated with elevated bilirubin levels and usually did not require discontinuation of therapy.
• Marked elevations of SGOT (> 1000 U/L) were seen before death in four patients with end-stage cardiac disease (severe congestive heart failure, cardiogenic shock).
• Rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment.
• It is recommended that patients in whom an abnormal liver test has occurred, or who have signs of symptoms suggesting liver dysfunction, be carefully evaluated.
• If persistent or worsening elevation of hepatic enzymes is detected, consideration should be given to discontinuing therapy.
• Blood Dyscrasias Among 10,867 patients treated with mexiletine in the compassionate use program, marked leukopenia (neutrophils less than 1000/mm 3 ) or agranulocytosis were seen in 0.06% and milder depressions of leukocytes were seen in 0.08%, and thrombocytopenia was observed in 0.16%.
• Many of these patients were seriously ill and receiving concomitant medications with known hematologic adverse effects.
• Rechallenge with mexiletine in several cases was negative.
• Marked leukopenia or agranulocytosis did not occur in any patient receiving mexiletine alone; five of the six cases of agranulocytosis were associated with procainamide (sustained release preparations in four) and one with vinblastine.
• If significant hematologic changes are observed, the patient should be carefully evaluated, and, if warranted, mexiletine should be discontinued.
• Blood counts usually return to normal within a month of discontinuation (see ADVERSE REACTIONS ).
• Convulsions (seizures) did not occur in mexiletine controlled clinical trials.
• In the compassionate use program, convulsions were reported in about 2 of 1000 patients.
• Twenty-eight percent of these patients discontinued therapy.
• Convulsions were reported in patients with and without a prior history of seizures.
• Mexiletine should be used with caution in patients with known seizure disorder.
• Drug Interactions Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations.
• Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential.
• Mexiletine was found to be non-mutagenic in the Ames test.
• Mexiletine did not impair fertility in the rat.
• Pregnancy Teratogenic Effects Reproduction studies performed with mexiletine in rats, mice and rabbits at doses up to four times the maximum human oral dose (24 mg/kg in a 50 kg patient) revealed no evidence of teratogenicity or impaired fertility but did show an increase in fetal resorption.
• Nursing Mothers Mexiletine appears in human milk in concentrations similar to those observed in plasma.
• Pediatric Use Safety and effectiveness in pediatric patients have not been established.
• General If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored.
• A limited number of patients (45 of 475 in controlled clinical trials) with preexisting first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block.
• Caution should be exercised when it is used in such patients or in patients with preexisting sinus node dysfunction or intraventricular conduction abnormalities.
• Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias.
• This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia:
• see ADVERSE REACTIONS ), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia.
• In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.
• Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.
• Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine.
• The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.
• Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy.
• The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.

• Teratogenic Effects Reproduction studies performed with mexiletine in rats, mice and rabbits at doses up to four times the maximum human oral dose (24 mg/kg in a 50 kg patient) revealed no evidence of teratogenicity or impaired fertility but did show an increase in fetal resorption.
• There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine hydrochloride is deemed essential, an alternative method of infant feeding should be considered.

• Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations.
• In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2.
• In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group.
• However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.
• In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine.
• Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QT c , RR, and PR intervals than propafenone alone.
• When concomitant administration of either of these two drugs is initiated, the dose of mexiletine should be slowly titrated to desired effect.
• In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions.
• A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy.
• When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported.
• Monitoring of mexiletine plasma levels is recommended during such concurrent use to
• avoid ineffective therapy.
• In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations.
• ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.
• Concurrent administration of cimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels; therefore patients should be followed carefully during concurrent therapy.
• Mexiletine does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to mexiletine, has been reported to lower serum digoxin levels.
• Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels.
• One controlled study in eight normal subjects showed a 72% mean increase (range 35 to 136%) in plasma theophylline levels.
• This increase was observed at the first test point which was the second day after starting mexiletine.
• Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine.
• If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed.
• An appropriate adjustment in theophylline dose should be considered.
• Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine.

• Clinical findings associated with mexiletine overdosage have included drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse and coma.
• The lowest known dose in a fatality case was 4.4 g with postmortem serum mexiletine level of 34 to 37 mcg/mL (Jequier P. et. al., Lancet 1976:
• 1 (7956):
• 429).
• Patients have recovered from ingestion of 4 g to 18 g of mexiletine (Frank S.
• E. et. al., Am J Emerg Med 1991: 9:43-48).
• There is no specific antidote for mexiletine.
• Management of mexiletine overdosage includes general supportive measures, close observation and monitoring of vital signs.
• In addition, the use of pharmacologic interventions (e.g., pressor agents, atropine or anticonvulsants) or transvenous cardiac pacing is suggested, depending on the patient’s clinical condition.