Action And Clinical Pharmacology: Mexiletine is a class 1B antiarrhythmic agent based on the classification system of Vaughan-Williams with local anesthetic properties, similar in structure and activity to lidocaine.
Mexiletine blocks the fast sodium channel in cardiac tissues, especially the Purkinje network, without involvement of the autonomic system. Mexiletine reduces the rate of rise and amplitude of the action potential and decreases automaticity (increases the threshold of excitability) in the Purkinje fibers. It shortens the action potential duration and, to a lesser extent, decreases the effective refractory period in the Purkinje fibers. It does not usually alter conduction velocity, although it may slow conduction in patients with pre-existing conduction abnormalities. In those with pre-existing sick sinus syndrome, mexiletine produces a more pronounced depression of the sinus rate and/or prolongation of sinus node recovery time. It does not significantly affect resting membrane potential or sinus node automaticity, left ventricular function, systolic arterial blood pressure, atrioventricular (AV) conduction velocity, or QRS or QT intervals.
Hemodynamic studies with oral mexiletine in patients with normal or abnormal myocardial function have shown that the drug has usually minor effects on cardiac output, pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, pulmonary diastolic pressure, blood pressure or heart rate. Small increases in vascular resistance without significant negative inotropic effects have also been observed.
Some studies with i.v. mexiletine showed evidence of impaired myocardial contractility after drug treatment. In patients with a history of cardiac decompensation, depression of heart function has been observed.
Mexiletine is well absorbed from gastrointestinal tract and peak plasma levels occur within 2 to 4 hours following an oral dose. Systemic bioavailability of mexiletine is about 90%. The apparent volume of distribution is large (5 to 10 L/kg) reflecting the extensive uptake of the drug by tissues. Protein binding of mexiletine has been estimated to be 55 to 70%.
The optimal plasma range is approximately 0.5 to 2 g/mL. The therapeutic efficacy as well as the frequency of side effects proportionately increases as the blood level rises. Little therapeutic response is seen with levels under 0.5 g/mL and a significant increase in side effects, particularly those in CNS, have been observed when plasma levels exceed 2 g/mL.
Mexiletine is primarily eliminated by hepatic metabolism with about 10% being excreted unchanged in urine. In man, the main metabolites are 4-hydroxy-mexiletine, hydroxymethyl mexiletine and their corresponding alcohols which are devoid of antiarrhythmic activity. The most active metabolite is N-methylmexiletine which is 20% as potent as mexiletine. The urinary excretion of this metabolite in man is less than 0.5%.
Mexiletine shows insignificant first pass elimination. In patients with ventricular arrhythmias, the elimination half-life (t 1/2) is about 12.1±4.0 hours (mean±SD) as compared to 9.7±1.9 hours in normal volunteers. The renal clearance of drug is increased by urinary acidosis.
Delayed and incomplete absorption as well as prolonged elimination (t 1/2 approximately 24 hours) has been associated with an acute myocardial infarction.
Prolongation of the t 1/2 was also observed in patients with hepatic impairment (t 1/2 approximately 25 hours), reduced renal function (creatinine clearance 10 mL/min: t 1/2=15.7 hours, creatinine clearance 11 to 40 mL/min: t 1/2=13.4 hours) and in patients free of hepatic or renal involvement but with severe left ventricular failure (t 1/2=about 15.4 hours±5.8 hours) (see Precautions, Drug Interactions).
Indications And Clinical Uses:
No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risk and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.
Mexiletine is indicated for the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Mexiletine may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of mexiletine its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.
For patients with sustained ventricular tachycardia, mexiletine therapy should be initiated in the hospital. Hospitalization may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.
The effects of mexiletine in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended.
Contra-Indications: In the presence of: known hypersensitivity to the drug or local anesthetics of amide type (e.g. pramoxine); second or third degree AV block in the absence of a pacemaker; cardiogenic shock.
Manufacturers’ Warnings In Clinical States: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in non-fatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.
The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.
Proarrhythmic Effects: Mexiletine has been reported to aggravate or induce arrhythmias in some patients. In the 398 patients studied in North American controlled clinical trials in whom evaluation was possible, mexiletine induced or aggravated pre-existing arrhythmias in 3.8%. The incidence as reported in the literature has ranged from 8 to 29%.
In the subgroup of patients with life-threatening arrhythmias subjected to programmed electrical stimulation or to exercise, 10 to 15% of the patients had exacerbation of their arrhythmias.
Precautions: Congestive Heart Failure or Hypotension: Mexiletine should be used with caution in such patients because of its potential for depressing myocardial contractility.
AV Block: If a ventricular pacemaker is operative, patients with second or third degree AV block may be treated with mexiletine if continuously monitored.
Conduction Abnormalities: Caution should be exercised when mexiletine is used in patients with first degree AV block, pre-existing sinus node dysfunction (e.g., sick sinus syndrome) or intraventricular conduction abnormalities.
Blood Dyscrasias: Blood dyscrasias were not seen in the controlled trials, but in the compassionate use program, leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported in a small number of patients. Although causal relationship has not been clearly established, such a relationship cannot be excluded. Therefore, it is recommended that careful hematologic monitoring should be carried out in patients on mexiletine. Hemogram including WBC differential and platelet count should be performed prior to initiation of therapy. If significant hematologic changes are observed, the patients should be carefully evaluated, and, if warranted, mexiletine should be discontinued. Blood counts usually returned to normal within one month of discontinuation (see Adverse Effects).
Patients with Liver Disease: 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.
Liver Injury: Abnormalities of the liver function and 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 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.
Urinary pH: Since renal excretion of mexiletine is highly increased with acidification of urine, concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during therapy.
Seizures: Mexiletine should be used with caution in patients with known seizure disorders. In the compassionate use programme, seizures were reported in approximately 0.2% of the patients with or without a prior history of seizures. Therapy was discontinued in 28% of those patients.
Occupational Hazards: Because mexiletine can cause CNS effects such as lightheadedness/dizziness, tremor and coordination difficulty, patients should be cautioned about engaging in activities requiring mental alertness, judgement and physical coordination (such as driving an automobile or operating machinery) when these effects occur.
Hypokalemia: Antiarrhythmic drugs may be ineffective in patients with hypokalemia. Therefore, any potassium deficit should be corrected as part of the management of ventricular arrhythmia.
Pregnancy: The safety of mexiletine in pregnancy has not been established. The expected benefits of using mexiletine when pregnancy is present or suspected must be weighed against possible hazards to the fetus. Studies in animals showed no embryotoxic nor teratogenic effects.
Lactation: It has been reported that mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine is deemed essential, an alternative method of infant feeding should be considered.
Children: The efficacy and safety of mexiletine in children has not been established and, therefore, its use in this age group is not recommended.
Drug Interactions: Tocainide/Lidocaine: Concomitant use of mexiletine and lidocaine or tocainide may lead to potentiation of adverse effects involving the CNS.
Other Cardiovascular Agents: Mexiletine has been used clinically with cardiac glycosides, other antiarrhythmic agents (quinidine, procainamide, disopyramide), diuretics and anticoagulants without evidence of serious untoward effects. In some cases addition of another antiarrhythmic achieved improved control of ventricular ectopy. It is however possible that concurrent use may produce additive effects and dosage adjustments may be necessary.
Mexiletine has no effect on digoxin serum levels.
Hepatic Enzyme Inducers: Drugs which induce hepatic enzymes such as phenytoin, rifampicin and phenobarbital increase non-renal clearance of mexiletine and therefore an increase in dosage may be required when these agents are started during mexiletine administration. Similarly, stopping therapy may call for a decrease in mexiletine dosage.
Cimetidine: Cimetidine has been reported to have a variety of effects on mexiletine absorption and plasma levels. During concurrent therapy, the patient should be carefully monitored for the emergence of adverse effects.
Theophylline: There have been rare reports of increased serum levels of theophylline following the concomitant administration of theophylline and mexiletine. Adverse effects typical of elevated serum levels of theophylline (i.e., nausea, vomiting, tremor) have occurred. Patients should be observed during concomitant therapy with the 2 drugs, and serum theophylline levels should be monitored. A reduction in the theophylline dose may be required.
Metoclopramide: Metoclopramide through its action on gastric motility, produces faster absorption and higher peak blood levels of mexiletine. No change in the maintenance dosage is required as bioavailability is not altered.
Agents which Alter Gastrointestinal Activity: Narcotic analgesics, anticholinergics and magnesium – aluminum hydroxide delay the absorption of mexiletine. The bioavailability and clearance of mexiletine are not altered and therefore no change in the maintenance dosage of mexiletine is recommended in patients receiving these drugs.
Adverse Reactions: The most common adverse reactions to mexiletine were upper gastrointestinal distress (22%), lightheadedness (8.6%) and tremor (8%). These were generally mild and were reversible with a reduction in dose or discontinuation of therapy. The adverse effect judged to be most severe was the induction or aggravation of pre-existing arrhythmia (see Warnings). Approximately 16% of patients had mexiletine discontinued because of side effects. Upper gastrointestinal distress was the adverse effect most commonly responsible for discontinuation of mexiletine.
Adverse experiences (incidence ³1%) (see Table I) were observed among 10 321 patients treated with mexiletine in controlled and open clinical trials. The majority of patients were seriously ill and undergoing multiple drug therapy.
Adverse effects occurring in less than 1% of patients are indicated below in decreasing order of incidence.
Cardiovascular: (0.1% to 1%) chest pain, hypotension, syncope, angina/angina-like pain, bradycardia, edema, hot flashes, atrioventricular block/conduction disturbances, hypertension.
CNS: (0.1% to 1%) short-term memory loss, speech difficulties, tinnitus, convulsions, hallucinations, psychosis, malaise.
Dermatological: (0.1% to 1%) diaphoresis, loss of hair, dry skin. Rare cases of exfoliative dermatitis and Stevens-Johnson Syndrome have been reported in association with mexiletine treatment.
Digestive: (0.1% to 1%) abdominal gas/bloating, dysphagia, hiccups, altered taste, salivary changes.
Genitourinary: (0.1% to 1%) impotence/decreased libido, urinary hesitancy/retention.
Hematological: thrombocytopenia (0.16 %), neutropenia (0.16%), agranulocytosis (0.16%), leukopenia (0.11%). Agranulocytosis was reported in 8 patients (including 2 patients with myelofibrosis) in the emergency use program. It occurred mostly after 1 to 6 weeks of therapy. All patients were als receiving procainamide and/or other drugs known to be associated with hematological disorders. Four patients died. Systemic Lupus Erythematosus was also reported in the emergency use program at a ratio of 4/10 000.
Other: (0.1% to 1%) arthralgia, difficulty swallowing, fever.
Laboratory: (0.1% to 1%) abnormal liver function tests, positive ANA.
Approximately 2% of the patients in the mexiletine compassionate use programme had elevations of AST greater than or equal to 3 times the upper limit of normal. These elevations frequently occurred in association with identifiable clinical events (e.g., CHF, myocardial infarction) and therapeutic measures (e.g., blood transfusion, other medications). These elevations were often asymptomatic and transient, usually not associated with elevated bilirubin levels and usually did not require discontinuation of mexiletine therapy. Marked elevations of AST (>1 000 U/L) were seen before death in 4 patients with end-stage cardiac disease (severe CHF, cardiogenic shock).
In foreign marketing experience, rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment (see Precautions).
In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including 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.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage of mexiletine has resulted in nausea, hypotension, bradycardia, paresthesia, left bundle branch block, asystole, convulsions and death.
Treatment: Should be supportive and may include gastric lavage and atropine for cardiovascular complications. Animal studies have shown that benzodiazepines protect against mexiletine induced convulsions. Acidification of the urine enhances mexiletine elimination.
Eleven cases of overdose have been reported; 3 were fatal. One fatality involved a healthy 22 year old male who ingested approximately 4.4 g of mexiletine. His symptoms were paresthesias, nausea and generalized convulsions.
On admission to the hospital, his pulse rate was 15 beats/minute, his blood pressure was unrecordable and an ECG showed complete heart block with a slow escape rhythm followed by ventricular asystole. He was unresponsive to all therapy. The blood level of mexiletine was 34 to 37 g/mL at the time of death.
Another fatality involved a male who started convulsing at home after taking an unknown quantity of mexiletine. The convulsions were uncontrolled by diazepam, phenytoin and phenobarbital and the patient died following aspiration and ventricular fibrillation. A post mortem at 26 hours found cardiac blood levels of 25 g/mL.
Details on the third fatality are not available.
Dosage And Administration: The optimal dosage should be individually determined based upon patient’s response and tolerance.
The recommended starting dose is 200 mg 3 times daily. This may be increased to a maximum of 1 200 mg daily, given in 3 or 4 divided doses. Dosage adjustment should take place in steps of 100 mg 3 times daily. A minimum of 3 days between each dosage change is required. The dosage usually associated with therapeutic response is between 600 and 900 mg daily. A small proportion of patients and those with severe liver disease may require smaller doses such as 100 mg 3 to 4 times daily, as such doses have been shown to provide effective plasma levels in some patients.
In patients in whom rapid control of ventricular arrhythmia is required, a loading dose of 400 mg may be administered. This should be followed by 200 mg given 3 times daily commencing 8 hours after the loading dose has been given.
Mexiletine should be administered with ample liquid, food and/or an antacid.
Information on the appropriate regimen for the transfer from i.v. lidocaine to mexiletine is lacking.
When transferring from lidocaine to mexiletine, the lidocaine infusion should be stopped when the first oral dose of mexiletine is administered. The infusion line should be kept in place in case the arrhythmia reappears and requires additional lidocaine to suppress it. Consideration should be given to the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.
Availability And Storage: 100 mg: Each orange/scarlet, hard, gelatin capsule contains: mexiletine HCl 100 mg. Nonmedicinal ingredients: colloidal silica, magnesium stearate and maize starch. Boxes of 100 (blister packed).
200 mg: Each scarlet, hard, gelatin capsule contains: mexiletine HCl 200 mg. Nonmedicinal ingredients: colloidal silica, magnesium stearate and maize starch. Boxes of 100 (blister packed).
Store between 15 and 30°C in an air-tight container.
MEXITIL® Boehringer Ingelheim Mexiletine HCl Antiarrhythmic
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