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mexiletine 150 mg capsule

In stock Manufacturer TEVA USA 00093873901
$0.89 / Capsule

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Uses

Ventricular Arrhythmias

Mexiletine hydrochloride is used for the treatment of documented ventricular arrhythmias (e.g., sustained ventricular tachycardia) that in the judgment of the clinician are life-threatening. Because of the drug's arrhythmogenic potential and the lack of evidence for improved survival, use of mexiletine for less severe arrhythmias is notrecommended.

Mexiletine hydrochloride can reduce VPCs, paired VPCs, and nonsustained ventricular tachycardia and can suppress the recurrence of ventricular tachycardia and/or fibrillation in patients with ventricular tachycardia and/or fibrillation. However, treatment of asymptomatic ventricular premature contractions (VPCs) should be avoided. (See Increased Mortality Associated with Antiarrhythmic Drugs under Warnings/Precautions: Warnings, in Cautions.) Mexiletine also has suppressed Holter monitor evidence of sustained ventricular tachycardia and ventricular tachycardia induced by programmed electrical stimulation (PES). In addition, mexiletine has been effective in some patients for the treatment of ventricular arrhythmias unresponsive to other antiarrhythmic agents.

Results of placebo- or comparative drug-controlled studies indicate that efficacy of mexiletine in reducing the frequency of VPCs, paired VPCs, and episodes of nonsustained ventricular tachycardia has been greater than that of placebo and similar to that of other class I antiarrhythmic agents (e.g., disopyramide, procainamide, quinidine).

Diabetic Neuropathy

Mexiletine hydrochloride has been used with equivocal results for the management of diabetic neuropathy. Efficacy has been evaluated in several randomized, placebo-controlled trials in a limited number of patients 45 years of age and older with prolonged painful diabetic neuropathy (for several months or years), who had long-standing (10 years or more) type 1 or 2 diabetes mellitus. Pain relief frequently was measured by a decrease in a visual analog pain score (VAS) using a 100-mm line as a pain scale. In a crossover study, about 67% (10 of 15) patients receiving mexiletine hydrochloride (10 mg/kg daily) experienced at least a 15-mm reduction in VAS score, while no patient receiving placebo experienced such a reduction. However, in a prospective, double-blind, placebo-controlled study, no statistically significant reduction in the VAS score was observed in patients receiving 600 mg of mexiletine hydrochloride daily when compared with those receiving placebo. The role of mexiletine in the management of diabetic neuropathy remains to be established; pending further accumulation of data from well-designed studies, use of the drug should be limited to patients who do not respond to, or who cannot tolerate, more established therapies.

Dosage and Administration

General

Mexiletine hydrochloride is administered orally every 8 hours. To minimize adverse GI effects, mexiletine should be taken with food or antacids.

Dosage of mexiletine hydrochloride should be individualized according to the patient's response, tolerance, general condition, and cardiovascular status. Clinical and ECG evaluation (e.g., Holter monitoring) is recommended to determine whether the desired antiarrhythmic effect has been achieved and to guide dosage titration and adjustment.

Ventricular Arrhythmias

For the treatment of life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia) in adults in whom rapid control of ventricular arrhythmia is essential, a 400-mg loading dose of mexiletine hydrochloride may be given, followed by a 200-mg dose in 8 hours. The onset of action is usually within 30-120 minutes.

In patients in whom rapid control of ventricular arrhythmia is not essential, the usual initial dosage of mexiletine hydrochloride is 200 mg every 8 hours. If necessary, dosage adjustments generally should be made at intervals of at least 2-3 days in increments or decrements of 50 or 100 mg. Satisfactory control of arrhythmias usually can be achieved at mexiletine hydrochloride dosages of 200-300 mg every 8 hours. If satisfactory control is not achieved in patients who tolerate well a mexiletine hydrochloride dosage of 300 mg every 8 hours, a dosage of 400 mg every 8 hours may be tried. Because adverse CNS effects are dose-related, daily dosage of mexiletine hydrochloride should not exceed 1.2 g. To improve compliance and convenience in some patients in whom an adequate control of arrhythmia has been achieved and are receiving mexiletine hydrochloride dosages of 300 mg or less every 8 hours, the total daily dosage may be given in a twice-daily dosing regimen (every 12 hours), while the degree of suppression of ventricular ectopy is closely monitored. If necessary, dosage may be increased up to a maximum of 450 mg every 12 hours.

When patients are switched to mexiletine from another class I oral antiarrhythmic agent; a single 200-mg dose of mexiletine hydrochloride may be given 6-12, 3-6, 6-12, or 8-12 hours after the last dose of quinidine sulfate, procainamide, disopyramide, or tocainide, respectively. Subsequent doses of mexiletine hydrochloride should be adjusted according to individual requirements. When patients are switched to mexiletine from IV lidocaine, the lidocaine infusion should be discontinued at the time of administration of the first dose of mexiletine hydrochloride; however, the infusion line should be kept open until the arrhythmia appears to be satisfactorily suppressed. In addition, since adverse effects associated with lidocaine and mexiletine may be additive, patients being switched from IV lidocaine to mexiletine should be closely monitored. Hospitalization is recommended for patients who are considered at high risk for developing life-threatening arrhythmias after discontinuance of existing antiarrhythmic therapy.

Diabetic Neuropathy

Although the optimal dosage regimen has not been fully determined, when mexiletine hydrochloride has been used in the treatment of painful diabetic neuropathy in adults, a low initial dosage (e.g., 200 mg once daily) has been used. Dosage then has been increased to 200 mg twice daily and 200 mg 3 times daily at 2-day intervals. Daily dosage of mexiletine hydrochloride generally should not exceed 1.2 g.

Special Populations

Hepatic Impairment

Dosage reduction should be considered in patients with hepatic impairment (including those with hepatic dysfunction secondary to right-sided congestive heart failure), since such conditions may decrease hepatic metabolism of the drug.

Renal Impairment

No dosage adjustment is required in patients with renal impairment.

Cautions

Contraindications

Mexiletine hydrochloride is contraindicated in patients with second- or third-degree AV block (unless a cardiac pacemaker is in place) or cardiogenic shock.

Warnings/Precautions

Warnings

Increased Mortality Associated with Antiarrhythmic Drugs

Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s postmarketing Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than 6 days but less than 2 years previously, indicate that the rate of total mortality and nonfatal cardiac arrest was increased in patients treated with encainide or flecainide compared with that seen in patients who received placebo. The average duration of encainide or flecainide therapy was 10 months. The applicability of these results to other populations (e.g., those without recent myocardial infarction) is uncertain. The manufacturers and many clinicians state that because of the drug's arrhythmogenic potential and the lack of evidence for improved survival for class I antiarrhythmic agents, use of mexiletine hydrochloride in patients with ventricular arrhythmias should be limited to those with life-threatening arrhythmias. Use of mexiletine for less severe arrhythmias currently is not recommended and treatment of asymptomatic VPCs should be avoided.

Major Toxicities

Cardiovascular Effects

Since mexiletine, like other antiarrhythmic agents, has been associated with development or exacerbation of arrhythmias in some patients, clinical and ECG evaluations are essential prior to and during mexiletine therapy to monitor for the appearance of arrhythmias and to determine the need for continued therapy. Because of the arrhythmogenic potential of the drug and the life-threatening nature of the arrhythmias against which the drug is being employed, the manufacturers recommend that mexiletine therapy be initiated in a hospital. Mexiletine should be used with caution in patients with preexisting first-degree AV block, sinus node dysfunction, or intraventricular conduction disturbances. Patients with second- or third-degree AV block and an operative ventricular pacemaker generally may receive mexiletine; however, such patients should be continuously monitored.(See Cautions: Contraindications.)

Since mexiletine may exacerbate hypotension and congestive heart failure, the drug should be used with caution in patients with these conditions.

Hepatic Effects

Abnormal liver function test results (elevations in AST [SGOT] more than 3 times the upper limit of normal) have been reported in some patients receiving mexiletine (frequently during initial weeks of therapy). Most of such patients had been diagnosed with congestive heart failure or acute myocardial infarction and/or had received blood transfusion or other drug therapies; a causal relationship to mexiletine has not been established. Elevated serum concentrations of hepatic enzymes generally were not accompanied by elevated bilirubin concentrations and discontinuance of mexiletine therapy usually was not required. Severe hepatic injury, including hepatic necrosis, also has been reported rarely in patients receiving mexiletine. The manufacturers recommend that patients who develop elevated serum concentrations of hepatic enzymes and those with signs or symptoms suggestive of liver dysfunction should be carefully evaluated; discontinuance of mexiletine therapy should be considered in patients with persistent or increasing enzyme elevations.

Blood Dyscrasias

Mild and marked leukopenia (neutrophil counts less than 1000/mm), agranulocytosis, and thrombocytopenia have been reported in patients receiving mexiletine. Many of these patients were severely ill and were receiving concurrent therapy with drugs known to cause adverse hematologic effects (e.g., procainamide, vinblastine). Patients who develop substantial hematologic changes should be carefully evaluated and discontinuance of mexiletine therapy considered. Blood cell counts usually return to normal within 1 month following discontinuance of the drug.

General Precautions

Seizures

Seizures have been reported rarely in patients (with or without prior history of seizures) receiving mexiletine; discontinuance of the drug occasionally has been necessary. Mexiletine should be used with caution in patients with a history of seizure disorder.

Effects on Urinary Excretion

Although urinary pH usually does not affect elimination of mexiletine, substantial changes in urinary pH may affect urinary excretion of the drug; therefore, concomitant drug therapy or dietary regimens that may markedly affect urinary pH should be avoided.

Specific Populations

Pregnancy

Category C.

Lactation

Mexiletine is distributed into milk at concentrations similar to those achieved in plasma. Discontinue nursing or drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of mexiletine in children have not been established.

Hepatic Impairment

Since mexiletine is metabolized in the liver, elimination may be prolonged in patients with hepatic impairment. Patients with hepatic impairment (including those with impairment secondary to congestive heart failure) should be carefully monitored while receiving mexiletine.(See Hepatic Impairment under Dosage and Administration: Special Populations)

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving mexiletine include nausea, vomiting, heartburn, diarrhea, constipation, changes in appetite, abdominal pain/discomfort, abdominal cramps, dry mouth, dizziness, lightheadedness, tremor, nervousness, weakness, fatigue, confusion/clouded sensorium, coordination difficulties, changes in sleep pattern, paresthesia or numbness, depression, headache, arthralgia, fever, blurred vision/visual disturbances, tinnitus, dyspnea, chest pain, palpitations, increased ventricular arrhythmia/ventricular premature contractions, angina or angina-like symptoms, rash, and non-specific edema. In controlled clinical trials, 40% of patients have discontinued the drug because of adverse effects.

During postmarketing surveillance, exacerbation of congestive heart failure (in patients with impaired ventricular function), pancreatitis, and pulmonary changes including pulmonary infiltration and pulmonary fibrosis (some patients had preexisting comorbidities and/or were receiving drugs with a potential for pulmonary toxicity), drowsiness, nystagmus, ataxia, dyspepsia, and hypersensitivity reaction have been reported in patients receiving mexiletine.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of mexiletine is mediated mainly by the cytochrome P-450 (CYP) isoenzymes, principally by the isoenzyme 2D6 and to a lesser extent by the isoenzyme 1A2. Therefore, inhibitors or inducers of these isoenzymes may increase or reduce plasma mexiletine concentrations, respectively.

Inducers of cytochrome P-450 (CYP) isoenzymes: Reductions in plasma mexiletine concentrations may occur in patients receiving mexiletine concurrently with hepatic enzyme inducers (e.g., phenobarbital, phenytoin, rifampin, rifapentine). When microsomal enzyme inducers are used in patients receiving mexiletine, plasma concentrations of mexiletine should be closely monitored to avoid subtherapeutic concentrations.

Inhibitors of the cytochrome P-450 (CYP) 3A4 or 1A2 isoenzymes: When concomitant use of fluvoxamine (an inhibitor of CYP1A2) or propafenone (an inhibitor of CYP2D6) with mexiletine is initiated, dosage of mexiletine should be slowly titrated to desired effect. Mexiletine clearance reportedly was reduced by 38% following concomitant single-dose administration of mexiletine with fluvoxamine; it is recommended that serum mexiletine concentrations be monitored. Following concomitant administration of mexiletine with propafenone in individuals with the poor-metabolizer phenotype, the pharmacokinetics of mexiletine were not affected in individuals with the poor-metabolizer phenotype; however, metabolic clearance of mexiletine decreased by about 70% in individuals with the extensive-metabolizer phenotype receiving these drugs concomitantly and, therefore, poor-metabolizers were indistinguishable from extensive-metabolizers. In this crossover steady-state study, pharmacokinetics of propafenone were not affected in individuals with the poor- or extensive-metabolizer phenotype receiving concomitant use with mexiletine. Administration of mexiletine in patients receiving propafenone did not result in any additional ECG changes (e.g., QRS, QTc, RR, PR intervals) compared with those receiving propafenone alone.

Cimetidine

Concomitant administration of cimetidine with mexiletine may result in increased, decreased, or unchanged plasma concentrations of mexiletine; plasma concentrations of mexiletine should be closely monitored during such concurrent use.

Methylxanthines

Pharmacokinetic interaction (decreased caffeine clearance, increased plasma theophylline concentration). Theophylline plasma concentrations should be monitored, especially after mexiletine hydrochloride dosage adjustments. Dosage adjustment of theophylline should be considered.

Drugs Affecting Gastric Emptying

Potential physiologic/pharmacokinetic interaction (gastric transit time can affect rate of absorption of mexiletine), since mexiletine is absorbed in the small intestine. Atropine, opiate agonists, and magnesium- and aluminum-containing antacids may slow absorption while metoclopramide may accelerate absorption of mexiletine.

Other Drugs

No adverse pharmacokinetic interactions were reported when mexiletine hydrochloride was used in patients receiving benzodiazepines, antianginal, antihypertensive, or anticoagulant drugs. Improved control of ventricular ectopy may occur in patients receiving other antiarrhythmic agents (e.g., quinidine, propranolol) concomitantly with mexiletine. No prolongation of the PR and QT interval or the QRS complex has been reported when mexiletine hydrochloride has been used concurrently with digoxin, diuretics, and/or propranolol.

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