Mexiletine Drug Information

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.

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.

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

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

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

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

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 -

Coordination Difficulties 9.7 1.1 1.3 - Changes in Sleep Habits 7.1 2.7

11.5

Weakness 5 5.3 7.7 2.9 Nervousness 5 1.9 6.4 5.8 Fatigue 3.8

5.7 5.1

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

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

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 events 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 with mexiletine treatment have been reported. Laboratory Abnormal liver function tests, about 5 in 1000; positive ANA and thrombocytopenia, each about 2 in 1000; leukopenia (including neutropenia and agranulocytosis), about 1 in 1000; myelofibrosis, about 2 in 10,000 patients. Other Diaphoresis, about 6 in 1000; altered taste, about 5 in 1000; salivary changes, hair loss and impotence/decreased libido, each about 4 in 1000; malaise, about 3 in 1000; urinary hesitancy/retention, each about 2 in 1000; hiccups, dry skin, laryngeal and pharyngeal changes and changes in oral mucous membranes, each about 1 in 1000; SLE syndrome, about 4 in 10,000. Hematology Blood dyscrasias were not seen in the controlled trials but did occur among 10,867 patients treated with mexiletine in the compassionate use program (see PRECAUTIONS ). Myelofibrosis was reported in two patients in the compassionate use program; one was receiving long-term thiotepa therapy and the other had pretreatment myeloid abnormalities.

In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and 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. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with preexisting compromised ventricular function.

There have been rare reports of pancreatitis associated with mexiletine treatment.

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

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 : 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.