Mexiletine Hydrochloride

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.

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

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 events reported in the one-month placebo-controlled trial. Table 1: Comparative Incidence (%) of Adverse Events 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 Events 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 …

Drung 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, QTc, 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. 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. There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit …

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. Electrophysiology in Man Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. In patients with normal conduction systems, mexiletine has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third degree AV block was observed. Mexiletine did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, mexiletine may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval. In patients with preexisting conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed. The antiarrhythmic effect of mexiletine has been established in controlled comparative trials against placebo, quinidine, procainamide and disopyramide. Mexiletine hydrochloride, at doses of 200 to 400 mg q8h, produced a significant reduction of ventricular premature beats, paired beats, and episodes of non-sustained ventricular tachycardia compared to placebo and was similar in effectiveness to the active agents. Among all patients entered into the studies, about 30% in each treatment group had a 70% or greater reduction in PVC count and about 40% failed to complete the 3 month studies because of adverse effects. Follow-up of patients from the controlled trials has demonstrated continued effectiveness of mexiletine in long-term use. Hemodynamics Hemodynamic studies in a limited number of patients, with normal or abnormal myocardial function, following oral administration of mexiletine hydrochloride, have shown small, usually not statistically significant, decreases in cardiac output and increases in systemic vascular resistance, but no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function, similar to that produced by lidocaine, has occasionally been observed following intravenous mexiletine therapy in patients with cardiac disease.

DESCRIPTION Mexiletine hydrochloride, USP is an orally active antiarrhythmic agent. It is a white or almost white crystalline powder, freely soluble in water, Methanol and sparingly soluble in Methylene Chloride. Mexiletine hydrochloride, USP has a pKa of 9.2. The chemical name of mexiletine hydrochloride, USP is 1- methyl-2-(2,6-xylyloxy)ethylamine hydrochloride and its structural formula is: C 11 H 17 NO. HCl M. W. 215.72 g/mole Each capsule for oral administration, contains 150 mg, 200 mg, or 250 mg of mexiletine hydrochloride, USP. 100 mg of mexiletine hydrochloride, USP is equivalent to 83.31 mg of mexiletine base. In addition, each capsule contains the following excipients: colloidal silicon dioxide, magnesium stearate and partially pregelatinized maize starch. The capsule shell contains D & C Yellow #10, gelatin and titanium dioxide. The 150 mg and 250 mg also contain FD&C Blue #1, FD&C Red #40, The 150 mg and 200 mg also contain FD&C Yellow #6. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water. The product complies with USP Dissolution Test 2. structure

OVERDOSAGE 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.

HOW SUPPLIED Mexiletine hydrochloride capsules USP, 150 mg are white opaque/light blue opaque colored size '2', hard gelatin capsules, imprinted with “V1” on cap and “30” on body, filled with white to off white granular powder. They are supplied as follows: Bottles of 100 NDC 31722-036-01 Mexiletine hydrochloride capsules USP, 200 mg are white opaque/light blue opaque colored size '1', hard gelatin capsules, imprinted with “V1” on cap and “33” on body, filled with white to off white granular powder. They are supplied as follows: Bottles of 100 NDC 31722-037-01 Mexiletine hydrochloride capsules USP, 250 mg are white opaque/light blue opaque colored size '0', hard gelatin capsules, imprinted with “V1” on cap and “34” on body, filled with white to off white granular powder. They are supplied as follows: Bottles of 100 NDC 31722-038-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). For more information, call Annora Pharma Private Limited at 1-866-495-1995. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 Manufactured by: Annora Pharma Private Limited Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District-502313 Telangana, India. Revised: 11/2022 mexiletine-hcl-caps-camber-logo