Mexiletine

Mechanism of Action Mexiletine hydrochloride is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, mexiletine has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.

INDICATIONS AND USAGE Mexiletine Hydrochloride Capsules USP are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of the physician, are life- threatening. Because of the proarrhythmic effects of mexiletine, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Initiation of mexiletine 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.

DOSAGE AND ADMINISTRATION The dosage of mexiletine hydrochloride must be individualized on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. Initiate mexiletine therapy with 200 mg every eight hours when rapid control of arrhythmia is not essential. A minimum of two to three days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down. As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment. Satisfactory control can be achieved in most patients by 200 to 300 mg given every eight hours with food or antacid. If satisfactory response has not been achieved at 300 mg q8h, and the patient tolerates mexiletine well, a dose of 400 mg q8h may be tried. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day. In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. Plasma level may also be affected by certain concomitant drugs (see PRECAUTIONS, Drug Interactions ). Loading Dose When rapid control of ventricular arrhythmia is essential, an initial loading dose of 400 mg of mexiletine hydrochloride may be administered, followed by a 200 mg dose in eight hours. Onset of therapeutic effect is usually observed within 30 minutes to two hours. Q12H Dosage Schedule Some patients responding to mexiletine may be transferred to a 12 hour dosage schedule to improve convenience and compliance. If adequate suppression is achieved on a mexiletine hydrochloride dose of 300 mg or less every eight hours, the same total daily dose may be given in divided doses every 12 hours while carefully monitoring the degree of suppression of ventricular ectopy. This dose may be adjusted up to a maximum of 450 mg every 12 hours to achieve the desired response. Transferring to Mexiletine Hydrochloride The following dosage schedule, based on theoretical considerations rather than experimental data, is suggested for transferring patients from other Class I oral antiarrhythmic agents to mexiletine: mexiletine hydrochloride treatment may be initiated with a 200 mg dose, and titrated to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last dose of disopryramide or 8 to 12 hours after the last dose of tocainide. In patients in whom withdrawal of the previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, hospitalization of the patient is recommended. When transferring from lidocaine to mexiletine, the lidocaine infusion should be stopped when the first oral dose of mexiletine hydrochloride is administered. The infusion line should be left open until suppression of the arrhythmia appears to be satisfactorily maintained. Consideration should be given to the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.

ADVERSE REACTIONS Mexiletine hydrochloride commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Mexiletine has been evaluated in 483 patients in one month and three month controlled studies and in over 10,000 patients in a large compassionate use program. Dosages in the controlled studies ranged from 600 to 1200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1600 to 3200 mg/day). In the three month controlled trials comparing mexiletine to quinidine, procainamide and disopyramide, the most frequent adverse reactions were upper gastrointestinal distress (41%), lightheadedness (10.5%), tremor (12.6%) and coordination difficulties (10.2%). Similar frequency and incidence were observed in the one month placebo-controlled trial. Although these reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, by taking the drug with food or antacid or by therapy discontinuation, they led to therapy discontinuation in 40% of patients in the controlled trials. Table 1 presents the adverse reactions reported in the one-month placebo-controlled trial. Table 1: Comparative Incidence (%) of Adverse Reactions Among Patients Treated with Mexiletine and Placebo in the 4 Week, Double-Blind Crossover Trial Mexiletine N = 53 Placebo N = 49 Cardiovascular Palpitations 7.5 10.2 Chest Pain 7.5 4.1 Increased Ventricular Arrythmia/PVCs 1.9 - Digestive Nausea/Vomiting/Heartburn 39.6 6.1 Central Nervous System Dizziness/Lightheadedness 26.4 14.3 Tremor 13.2 - Nervousness 11.3 6.1 Coordination Difficulties 9.4 - Changes in Sleep Habits 7.5 16.3 Paresthesias/Numbness 3.8 2 Weakness 1.9 4.1 Fatigue 1.9 2 Tinnitus 1.9 4.1 Confusion/Clouded Sensorium 1.9 2 Other Headache 7.5 6.1 Blurred Vision/Visual Disturbances 7.5 2 Dyspnea/Respiratory 5.7 10.2 Rash 3.8 2 Non-specific Edema 3.8 - Table 2 presents the adverse reactions occurring in one percent or more of patients in the three month controlled studies. Table 2: Comparative Incidence (%) of Adverse Reactions Among Patients Treated with Mexiletine or Control Drugs in the 12 Week Double-Blind Trials Mexiletine N = 430 Quinidine N = 262 Procainamide N = 78 Disopyramide N = 69 Cardiovascular Palpitations 4.3 4.6 1.3 5.8 Chest Pain 2.6 3.4 1.3 2.9 Angina/Angina-like Pain 1.7 1.9 2.6 2.9 Increased Ventricular Arrhythmias/PVCs 1 2.7 2.6 - Digestive Nausea/Vomiting/Heartburn 39.3 21.4 33.3 14.5 Diarrhea 5.2 33.2 2.6 8.7 Constipation 4 - 6.4 11.6 Changes in Appetite 2.6 1.9 - - Abdominal Pain/Cramps/Discomfort 1.2 1.5 - 1.4 Central Nervous System Dizziness/Lightheadedness 18.9 14.1 14.1 2.9 Tremor 13.2 2.3 3.8 1.4 Coordination Difficulties 9.7 1.1 1.3 - Changes in Sleep Habits 7.1 2.7 11.5 8.7 Weakness 5 5.3 7.7 2.9 Nervousness 5 1.9 6.4 5.8 Fatigue 3.8 5.7 5.1 1.4 Speech Difficulties 2.6 0.4 - - Confusion/Clouded Sensorium 2.6 - 3.8 - Paresthesias/Numbness 2.4 2.3 2.6 - Tinnitus 2.4 1.5 - - Depression 2.4 1.1 1.3 1.4 Other Blurred Vision/Visual Disturbances 5.7 3.1 5.1 7.2 Headache 5.7 6.9 7.7 4.3 Rash 4.2 3.8 10.3 1.4 Dyspnea/Respiratory 3.3 3.1 5.1 2.9 Dry Mouth 2.8 1.9 5.1 14.5 Arthralgia 1.7 2.3 5.1 1.4 Fever 1.2 3.1 2.6 - Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of consciousness, other psychological changes, diaphoresis, urinary hesitancy/retention, malaise, impotence/decreased libido, pharyngitis, congestive heart failure. An additional group of over 10,000 patients has been treated in a program allowing administration of mexiletine hydrochloride under compassionate use circumstances. These patients were seriously ill with the large majority on multiple drug therapy. Twenty-four percent of the patients continued in the program for one year or longer. Adverse reactions leading to therapy discontinuation occurred in 15 percent of patients (usually upper gastrointestinal system or nervous system effects). In general, the more common adverse reactions were similar to those in the controlled trials. Less common adverse reactions possibly related to mexiletine use include: Cardiovascular System Syncope and hypotension, each about 6 in 1000; bradycardia, about 4 in 1000; angina/angina-like pain, about 3 in 1000; edema, atrioventricular block/conduction disturbances and hot flashes, each about 2 in 1000; atrial arrhythmias, hypertension and cardiogenic shock, each about 1 in 1000. Central Nervous System Short-term memory loss, about 9 in 1000 patients; hallucinations and other psychological changes, each about 3 in 1000; psychosis and convulsions/seizures, each about 2 in 1000; loss of consciousness, about 6 in 10,000. Digestive Dysphagia, about 2 in 1000; peptic ulcer, about 8 in 10,000; upper gastrointestinal bleeding, about 7 in 10,000; esophageal ulceration, about 1 in 10,000. Rare cases of severe hepatitis/acute hepatic necrosis. Skin Rare cases of exfoliative dermatitis and Stevens-Johnson syndrome

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. 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.