warnings
WARNINGS Mortality Ethmozine® was one of the three antiarrhythmic drugs included in the National Heart Lung and Blood Institute's (NHLBI) Cardiac Arrhythmia Suppression Trial (CAST I), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had a myocardial infarction more than six days, but less than two years previously. An excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with both of the Class IC agents included in the trial, which led to discontinuation of those two arms of the trial. The average duration of treatment with these agents was 10 months. The Ethmozine® and placebo arms of the trial were continued in the NHLBI-sponsored CAST II. In this randomized, double-blind trial, patients with asymptomatic, non-life-threatening ventricular arrhythmias who had had a myocardial infarction within 4 to 90 days and left ventricular ejection fraction ≤0.40 prior to enrollment were evaluated. The average duration of treatment with Ethmozine® in this study was 18 months. The study was discontinued because of the unlikely possibility of demonstrating a benefit toward improved survival with Ethmozine® and because of an evolving adverse trend after long-term treatment, although there was no statistical significance versus placebo. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of Ethmozine® and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Ethmozine®, as well as other antiarrhythmic agents, should be reserved for patients with life-threatening ventricular arrhythmias. Proarrhythmia Like other antiarrhythmic drugs, Ethmozine® can provoke new rhythm disturbances or make existing arrhythmias worse. These proarrhythmic effects can range from an increase in the frequency of VPDs to the development of new or more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. It is often not possible to distinguish a proarrhythmic effect from the patient's underlying rhythm disorder, so that the occurrence rates given below must be considered approximations. Note also that drug-induced arrhythmias can generally be identified only when they occur early after starting the drug and when the rhythm can be identified, usually because the patient is being monitored. It is clear from the NIH sponsored CAST (Cardiac Arrhythmia Suppression Trial) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole that do not appear early after treatment but that represent a sustained increased risk. Domestic pre-marketing trials included 1072 patients given Ethmozine®; 397 had baseline lethal arrhythmias (sustained VT or VF and non-sustained VT with hemodynamic symptoms) and 576 had potentially lethal arrhythmias (increased VPDs or NSVT in patients with known structural heart disease, ischemic heart disease, congestive heart failure or an LVEF <40% and/or Cl <2.01/min/m2). In this population there were 40 (3.7%) identified proarrhythmia events, 26 (2.5%) of which were serious, either fatal (6), new hemodynamically significant sustained VT or VF (4), new sustained VT that was not hemodynamically significant (11) or sustained VT that became syncopal/presyncopal when it had not been before (5). Proarrhythmic effects described as incessant ventricular tachycardia were observed in the post-marketing PES study and in post-marketing adverse event reports. In general, serious proarrhythmic effects in the domestic pre-marketing trials were equally common in patients with more and less severe arrhythmias, 2.5% in the patients with baseline lethal arrhythmias vs. 2.8% in patients with potentially lethal arrhythmias, although the patients with serious effects were more likely to have a history of sustained VT (38% vs. 23%). In the post-marketing comparative PES study, patients treated with Ethmozine® (250-300 mg TID) had a proarrhythmia rate of 14% (8/59). Five of the six fatal proarrhythmic events were in patients with baseline lethal arrhythmias; four had prior cardiac arrests. Rates and severity of proarrhythmic events were similar in patients given 600-900 mg of Ethmozine® per day and those given higher doses. Patients with proarrhythmic events were more likely than the overall population to have coronary artery disease (85% vs. 67%), history of acute myocardial infarction (75% vs. 53%), congestive heart failure (60% vs. 43%), and cardiomegaly (55% vs. 33%). All of the six proarrhythmic deaths were in patients with coronary artery disease; 5/6 each had documented acute myocardial infarction, congestive heart failure, and cardiomegaly. Electrolyte Disturbances Hypokalemia, hyperkalemia or hypomagnesemia may alter the effects of Class I antiarrhythmic drugs. Electrolyte imbalances should be corrected before administration of Ethmozine®. Sick Sinus Syndrome Ethmozine® should be used only with extreme caution in patients with sick sinus syndrome, as it may cause sinus bradycardia, sinus pause or sinus arrest.