Mexitil

Mexiletine is used to treat certain types of ventricular arrhythmias (abnormal heart rhythms). Mexiletine is in a class of medications called antiarrhythmics. It works by blocking certain electrical signals in the heart to stabilize the heart rhythm.

See also Warning section.Nausea, vomiting, heartburn, dizziness, lightheadedness, vision problems (such as blurred vision), headache, shaking, nervousness, or problems with muscle control (coordination difficulties) may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor immediately if any of these rare but serious side effects occur: worsening symptoms of heart failure (such as ankle/leg swelling, increased tiredness, increased shortness of breath when lying down), signs of liver problems (such as persistent nausea/vomiting, stomach/abdominal pain, yellowing eyes/skin, dark urine).Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, seizure.A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Mexiletine may cause you to have abnormal liver function tests, especially if you also have congestive heart failure, or blood circulation problems.

Call your doctor at once if you have:

• chest pain;
• a new or a worsening irregular heartbeat pattern; or
• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• heartburn, upset stomach, nausea, vomiting;
• dizziness, feeling lightheaded;
• tremors, feeling nervous;
• problems with coordination; or
• blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Mexitil is a prescription medication used to treat life-threatening, ventricular arrhythmias (irregular heartbeats).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Mexitil is part of the drug class:

• Antiarrhythmics, class Ib

Mexiletine affects the way that your heart beats.

Mexiletine is used to treat seriously irregular heartbeats.

Mexiletine may also be used for purposes not listed in this medication guide.

Contraindications

• Second- or third-degree AV block (unless a cardiac pacemaker is in place).1 34 46

• Cardiogenic shock.1 34 46

Warnings/Precautions

Warnings

Mortality

In CAST study, excessive rate of mortality and nonfatal cardiac arrest reported in patients with asymptomatic, non-life-threatening ventricular arrhythmias and recent MI (>6 days but <2 years previously) who were receiving encainide or flecainide compared with placebo.1 2 3 4 5 34

Limit use of mexiletine in patients with ventricular arrhythmias to those with life-threatening arrhythmias1 34 due to mexiletine’s arrhythmogenic potential (see Cardiovascular Effects under Cautions) and the lack of evidence for improved survival for class I antiarrhythmic agents.33 34 40 41 42 Use for treatment of less severe arrhythmias currently is not recommended; avoid treatment of asymptomatic VPCs.1 34

Major Toxicities

Cardiovascular Effects

Possible development or exacerbation of arrhythmias; clinical and ECG evaluations are essential prior to and during therapy.1 34 Initiate therapy in a hospital.1 34

Use with caution in patients with preexisting first-degree AV block, sinus node dysfunction, or intraventricular conduction disturbances.1 34 Continuous monitoring recommended for patients with second- or third-degree AV block and an operative ventricular pacemaker.1 34 (See Contraindications under Cautions.)

Possible exacerbation of hypotension and CHF; use with caution in patients with these conditions.1 34

Hepatic Effects

Possible abnormal liver function test results (AST elevations ≥3 times the ULN),1 34 44 especially during initial weeks of therapy in patients with CHF or AMI and/or patients who have received blood transfusions or other drug therapies.1 34 Discontinuance of therapy usually is not required.1 34 Severe hepatic injury, including hepatic necrosis, reported rarely.1 34

Carefully evaluate patients who develop elevated serum concentrations of hepatic enzymes and those with signs or symptoms suggestive of liver dysfunction; consider discontinuance of therapy if enzyme elevations are persistent or increasing.1 34

Hematologic Effects

Possible leukopenia, agranulocytosis, and thrombocytopenia, 1 34 especially in severely ill patients receiving concurrent therapy with drugs known to cause adverse hematologic effects (e.g., procainamide, vinblastine).1 34

Carefully evaluate patients in whom substantial hematologic changes occur; consider discontinuing therapy.1 34 Blood cell counts generally return to normal within 1 month following discontinuance.1 34

General Precautions

Seizures

Seizures reported rarely; discontinuance of therapy may be necessary.1 34 Use with caution in patients with a history of seizure disorder.1 34

Effects on Urinary Excretion

Substantial changes in urinary pH may affect urinary excretion of mexiletine; avoid concomitant drug therapy or dietary regimens that may markedly affect urinary pH.1 11 12 21 34

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk.1 21 34 Discontinue nursing or the drug.1 34

Pediatric Use

Safety and efficacy not established.1 34 44 47

Hepatic Impairment

Possible prolonged elimination.1 8 9 12 13 34 Careful monitoring recommended (including in those with hepatic impairment secondary to CHF).1 8 9 34 Consider dosage reduction.1 8 12 34 44

Common Adverse Effects

Nausea,1 14 18 19 20 34 vomiting,1 18 19 20 34 heartburn,1 14 20 34 dizziness1 5 18 19 34 or lightheadedness,1 34 tremor,1 18 20 34 nervousness,1 34 chest pain, 1 34 coordination difficulties,1 34 headache,1 15 34 blurred vision/visual disturbances.1 20 34

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Mexiletine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	150 mg*	Mexiletine Hydrochloride Capsules
			Mexitil	Boehringer Ingelheim
		200 mg*	Mexiletine Hydrochloride Capsules
			Mexitil	Boehringer Ingelheim
		250 mg*	Mexiletine Hydrochloride Capsules
			Mexitil	Boehringer Ingelheim

Mexitil® (mexiletine hydrochloride, USP) is an orally active antiarrhythmic agent available as 150 mg, 200 mg and 250 mg capsules. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. Mexitil has a pKa of 9.2.

Chemically, Mexitil is 1-methyl-2-(2, 6-xylyloxy) ethylamine hydrochloride and has the following structural formula:

Mexitil capsules contain the following excipients: colloidal silicon dioxide, corn starch, magnesium stearate, titanium dioxide, gelatin, pharmaceutical glaze, simethicone, FD&C Red No. 40, and FD&C Blue No. 1; the Mexitil 150 mg and 250 mg capsules also contain FD&C Yellow No. 10 and D&C Red No. 28. Mexitil capsules may contain one or more of the following components: sodium lauryl sulfate, lecithin, shellac, and FD&C Blue No. 1 Aluminum Lake.

Mexitil (mexiletine hydrochloride, USP)is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgement of the physician, are life-threatening. Because of the proarrhythmic effects of Mexitil, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of Mexitil treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital.

Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

General

If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with Mexitil (mexiletine hydrochloride, USP) if continuously monitored. A limited number of patients (45 of 475 in controlled clinical trials) with pre-existing first degree AV block were treated with Mexitil; 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 pre-existing sinus node dysfunction or intraventricular conduction abnormalities.

Like other antiarrhythmics Mexitil (mexiletine hydrochloride, USP) can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or non-sustained 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, 10-15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.

Mexitil should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.

Since Mexitil is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of Mexitil, patients with liver disease should be followed carefully while receiving Mexitil. 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 Mexitil therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of Mexitil.

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 Mexitil treatment. It is recommended that patients in whom an abnormal liver test has occurred, or who have signs or 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/mm3) 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 Mexitil 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, Mexitil should be discontinued. Blood counts usually return to normal within one month of discontinuation. (See ADVERSE REACTIONS).

Convulsions (seizures) did not occur in Mexitil 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 Mexitil 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, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect.

In a large compassionate use program Mexitil 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 Mexitil®, lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy.

In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol.

Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy.

Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil (mexiletine hydrochloride, USP) Capsules, has been reported to lower serum digoxin levels.

Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil. Theophylline plasma levels returned to pre- Mexitil values within 48 hours after discontinuing Mexitil. If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil 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 Mexitil.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential. Mexitil was found to be non-mutagenic in the Ames test. Mexitil did not impair fertility in the rat.

Pregnancy/Teratogenic Effects PREGNANCY CATEGORY C

Reproduction studies performed with Mexitil (mexiletine hydrochloride, USP) 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.

Nursing Mothers

Mexitil appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of Mexitil is deemed essential, an alternative method of infant feeding should be considered.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Applies to mexiletine: oral capsule

General

Generally, mexiletine (the active ingredient contained in Mexitil) has been well tolerated. Side effects usually have been reversible and dose-related. The most common side effects associated with mexiletine therapy have been gastrointestinal and nervous system effects. The incidence of side effects increases at serum levels greater than 2.0 mcg/mL.[Ref]

Gastrointestinal

A case of mexiletine (the active ingredient contained in Mexitil) esophageal ulceration has been reported. Mexiletine was continued following a dosage reduction and an increase in the dosing interval.[Ref]

Gastrointestinal side effects have occurred most frequently. Nausea, anorexia, constipation and dyspepsia have been reported in 10% to 40% of patients, primarily during the first 3 to 4 weeks of therapy. Administration with food usually reduced gastrointestinal side effects. Diarrhea was reported in 7% of patients. Dysphagia, salivary changes, altered taste, changes in oral mucosa, hiccups, peptic ulcer disease, upper GI bleeding, and esophageal ulceration have been reported rarely.[Ref]

Nervous system

Nervous system side effects have included fine hand tremor (10%), dizziness (up to 25%), and difficulties with coordination (10.2%). These symptoms may be the first signs of toxicity. Ataxia, dysarthria, drowsiness, paresthesias, nervousness, speech difficulties, depression, and confusion have been reported less frequently. Short-term memory loss, malaise, seizures, and loss of consciousness have occurred.[Ref]

Cardiovascular

Cardiovascular symptoms of palpitation and chest pain have occurred in up to 7.5% of patients. A proarrhythmic effect has been reported in approximately 10% of patients and angina 1.7%. Mexiletine (the active ingredient contained in Mexitil) has little effect on cardiac contractility. Syncope, hypotension, hypertension, bradycardia, conduction disturbances, atrial arrhythmias, edema, and congestive heart failure have occurred.[Ref]

Rare cases of torsades de pointes have been associated with mexiletine. New or worsened congestive heart failure has been reported in 1% to 3% of patients.

A case of new first-degree AV heart block and left bundle branch block associated with elevated mexiletine serum levels (34 mcg/mL) was reported.[Ref]

Hematologic

Hematologic side effects are rare and have included reports of thrombocytopenia, which is thought to be due to an IgM cold agglutinin.[Ref]

Hypersensitivity

A generalized pruritic, erythematous, papular rash has been reported in a 77-year-old man.[Ref]

Hypersensitivity rashes have been reported rarely.[Ref]

Hepatic

Hepatic side effects have been rare. Isolated cases of mild reversible elevations in liver function tests which resolved after two to three weeks after stopping mexiletine (the active ingredient contained in Mexitil) have occurred. Rare cases of severe hepatitis or acute hepatic necrosis have been reported.[Ref]

Respiratory

Respiratory abnormalities including dyspnea have occurred in 3.7% to 5.7% of patients.[Ref]

A case of fatal diffuse interstitial pulmonary fibrosis has been associated with mexiletine in a 75-year-old man who had previously taken procainamide and disopyramide. Symptoms of dyspnea preceded chest X-ray abnormalities by months. The diagnosis was made following pulmonary function tests, chest CT scan, and an open lung biopsy.[Ref]

Ocular

Ocular side effects including diplopia, nystagmus, and blurred vision have been reported in up to 7.5% of patients.[Ref]

Dermatologic

Dermatologic side effects have been uncommon, however, rash has been reported in up to 4.2% of patients. Rare cases of exfoliative dermatitis and Stevens-Johnson Syndrome have occurred. Diaphoresis, hot flashes, and dry skin have been reported.[Ref]

Genitourinary

Genitourinary side effects including urinary hesitancy and retention have occurred rarely. Impotence and decreased libido have been reported.[Ref]

Psychiatric

Psychiatric side effects including psychosis and hallucinations have been reported.[Ref]

Some side effects of Mexitil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.