Mexiletine Hydrochloride 150 mg Capsule, 100-count

WARNINGS BOXED WARNING WARNINGS Mortality In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind s tudy in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%).

The average duration of treatment with encainide or flecainide in this study was ten months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of mexiletine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of mexiletine as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmia.

Acute Liver Injury In postmarketing experience abnormal liver function tests have been reported, some in the first few weeks of therapy with mexiletine hydrochloride. Most of these have been observed in the setting of congestive heart failure or is chemia and their relationship to mexiletine hydrochloride has not been established. Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS) Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking mexiletine.

DRESS typically presents with eosinophilia, fever, rash, and/or lymphadenopathy in association with other organ involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Discontinue mexiletine if DRESS is suspected.

Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS) Drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking mexiletine. DRESS typically presents with eosinophilia, fever, rash, and/or lymphadenopathy in association with other organ involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Discontinue mexiletine if DRESS is suspected.

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 600-1,200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1,600-3,200 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

10.2Chest Pain 7.5

4.1Increased Ventricular Arrhythmia /PVC's 1.9 - Digestive Nausea/Vomiting/Heartburn 39.6

6.1Central Nervous System Dizziness/Lightheadedness 26.4

14.3Tremor 13.2 — Nervousness 11.3

6.1Coordination Difficulties 9.4 — Changes in Sleep Habits 7.5

16.3Paresthesias/Numbness 3.8

2.0Weakness 1.9

4.1Fatigue 1.9

2.0Tinnitus 1.9

4.1Confusion/Clouded Sensorium 1.9

2.0Other Headache 7.5

6.1Blurred Vision/Visual Disturbances 7.5

2.0Dyspnea/Respiratory 5.7

10.2Rash 3.8

2.0Non-specific Edema 3.8 — Table 2: Comparative Incidence (%) of Adverse Events Among Patients Treated with Mexiletine or Control Drugs in the 12-Week Double-blind Trials Table 2 presents the adverse reactions occurring in one percent or more of patients in the three-month controlled studies. Mexiletine N = 430 Quinidine N = 262 Procainamide N = 78 Disopyramide N = 69 Cardiovascular Palpitations 4.3 4.6 1.3

5.8Chest Pain 2.6 3.4 1.3

2.9Angina/Angina-like Pain 1.7 1.9 2.6

2.9Increased Ventricular Arrhythmias/PVC's 1.0 2.7 2.6 — Digestive Nausea/Vomiting/Heartburn 39.3 21.4 33.3

14.5Diarrhea 5.2 33.2 2.6

8.7Constipation 4.0 — 6.4

11.6Changes in Appetite 2.6 1.9 — — Abdominal Pain/Cramps/Discomfort 1.2 1.5 —

1.4Central Nervous System Dizziness/Lightheadedness 18.9 14.1 14.1

2.9Tremor 13.2 2.3 3.8

1.4Coordination Difficulties 9.7 1.1 1.3 — Changes in Sleep Habits 7.1 2.7 11.5

8.7Weakness 5.0 5.3 7.7

2.9Nervousness 5.0 1.9 6.4

5.8Fatigue 3.8 5.7 5.1

1.4Speech 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

1.4Other Blurred Vision/Visual Disturbances 5.7 3.1 5.1

7.2Headache 5.7 6.9 7.7

4.3Rash 4.2 3.8 10.3

1.4Dyspnea/ Respiratory 3.3 3.1 5.1

2.9Dry Mouth 2.8 1.9 5.1

14.5Arthralgia 1.7 2.3 5.1

1.4Fever 1.2 3.1 2.6 — 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 events possibly related to mexiletine use include:Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of co…

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, QTc, RR, and PR intervals than propafenone alone.

When concomitant administration of either of these two drugs is initiated with mexiletine, 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%-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.