Mortality ENKAID was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study 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 nonfatal cardiac arrest rate was seen in patients treated with ENKAID compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 40/415 (9.6%) for ENKAID and 15/416 (3.6%) for the matched placebo. The average duration of treatment with ENKAID in this study was ten months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain, but at present it is prudent to consider the risks of Class 1c agents (including ENKAID), coupled with the lack of any evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.
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WARNINGS Mortality ENKAID was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study 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 nonfatal cardiac arrest rate was seen in patients treated with ENKAID compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 40/415 (9.6%) for ENKAID and 15/416 (3.6%) for the matched placebo. The average duration of treatment with ENKAID in this study was ten months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain, but at present it is prudent to consider the risks of Class 1c agents (including ENKAID), coupled with the lack of any evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs. Proarrhythmia ENKAID, like other antiarrhythmic agents, can cause new or worsened arrhythmias. Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia; eg, tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In patients with malignant arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient’s underlying rhythm disorder from drug induced worsening, so the following occurrence rates must be considered approximations. Overall, in premarketing clinical trials with ENKAID about 10% of all patients had proarrhythmic events, about 6% of them representing new or worsened ventricular tachycardia. Provocation or aggravation occurred most frequently in patients who had a history of sustained ventricular tachycardia (12% of such patients), cardiomyopathy (16%), congestive heart failure (12%), or sustained ventricular tachycardia with cardiomyopathy or congestive heart failure (17%). The incidence of proarrhythmic events in patients without ventricular tachycardia or overt manifestations of clinical heart disease ranged from 3% to 4%. Proarrhythmia occurred least frequently in patients with no known structural heart disease. Age, sex, baseline ECG intervals, or ECG changes caused by ENKAID were not predictive of the occurrence of proarrhythmia. A review of deaths in premarketing clinical trials indicates that about 1% of patients might have died of a possible proarrhythmic effect of ENKAID, virtually all of them patients with a history of ventricular tachycardia. In most cases, patients had a history of sustained ventricular tachycardia or ventricular fibrillation. Proarrhythmic events in premarketing clinical trials occurred most commonly during the first week of therapy and were much more common when doses exceeded 200 mg/day. Initiating therapy at 75 mg/day combined with gradual dose adjustment reduced the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION ). Congestive Heart Failure New or worsened congestive heart failure (CHF) attributed to ENKAID occurred infrequently (< 1%); nevertheless, ENKAID should be used cautiously in patients with CHF or congestive cardiomyopathy. Electrolyte Disturbances Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of ENKAID. Sick Sinus Syndrome — (Bradycardia-Tachycardia Syndrome) ENKAID should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest. Electrocardiographic Changes ENKAID slows conduction and consequently produces dose-related changes in the PR and QRS intervals. The intervals increase in a linear manner at doses from 30 to 225 mg/day. There is no consistent change in the JT. The QTc interval is increased, but only to the extent of the increase in QRS interval. *Percent change based on mean baseline values of PR = 0.169 and QRS = 0.088 from a group of 504 patients treated for ventricular arrhythmias. Changes in ECG Intervals* Total Daily Dose (mg) 75 150 200 Interval sec (%) sec (%) sec (%) PR 0.02 (12) 0.04 (21) 0.04 (24) QRS 0.01 (12) 0.02 (23) 0.02 (26) Unlike the changes in the PR, QRS, and QTc intervals observed with the Class IA drugs, the ECG changes induced by ENKAID are not in themselves indications of effectiveness, toxicity or overdosage nor can they routinely be used to predict efficacy. Clinically significant changes in cardiac conduction have been observed. Sinus bradycardia, sinus pause, or sinus arrest occurred in 1% of the patients and prolongation of QRS interval to greater than/or equal to 0.20 sec developed in about 7% of the patients. The incidence of second- or third-degree AV block was less, 0.5% and 0.2% respectively. Effects on Pacemaker Thresholds The safety of ENKAID in patients with permanently implanted programmable pacemakers has been established in a small (10 patient) study which evaluated the effects of increasing doses on pacemaker thresholds. ENKAID has a limited potential for increasing pacemaker thresholds. Only one subject had a clinically significant change that would require pacemaker reprogramming and that occurred only at the highest dose tested (75 mg t.i.d.). These effects were reversed when the drug was discontinued. It is advisable to establish pacemaker threshold prior to encainide administration and at regular intervals during therapy. Reprogramming of multi-programmable pacemakers may be required to increase voltage or pulse width. ENKAID should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available. In addition to possible rise in pacing threshold, ENKAID may suppress ventricular escape rhythms.
ADVERSE REACTIONS In the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), the incidence of total mortality and nonfatal cardiac arrest in the ENKAID group was 40/415 (9.6%) and that in the placebo group was 15/416 (3.6%). (See boxed WARNINGS ). The most serious adverse reactions reported for ENKAID in premarketing clinical trials were the provocation or aggravation of ventricular arrhythmias (See WARNINGS ). These occurred during the course of the clinical research program in about 10% of the patients who received a wide range of doses under a variety of circumstances. In some cases this resulted in the development of sustained ventricular tachycardia or ventricular fibrillation. Only 0.4% of patients discontinued ENKAID therapy due to congestive heart failure or related causes. Second- or third-degree AV block developed in 0.5% and 0.2% of the patients, respectively. Sinus bradycardia, sinus pause or sinus arrest occurred in 1% of patients. There have been rare reports of elevated serum liver enzymes (alkaline phosphatase, serum transaminase), hepatitis, and jaundice, in which a relation to encainide is possible and there has been one instance of a rechallenge-confirmed elevation of transaminases. There have also been rare reports of elevated blood glucose levels or of increased insulin requirements in diabetic patients. Although no cause and effect relationship has been established, caution is advised in patients who develop unexplained jaundice or signs of hepatic dysfunction or hyperglycemia and consideration should be given to discontinuing therapy. In premarketing evaluations, 2400 subjects were exposed to ENKAID, of whom more than 500 were maintained on drug for two years or longer. Adverse events were sufficiently troublesome to cause discontinuation in about 7% of the patients participating in premarketing clinical trials. The most frequently reported adverse events were dizziness, blurred or abnormal vision, and headache. The following table lists the most common adverse events that occurred in two multi-center premarketing clinical trials, one of which compared encainide to placebo, the other to quinidine. This table lists all such adverse events reported by at least 3% of the patients and thus may include symptoms of the underlying disease, intercurrent illness or adverse reactions to drug therapy. Incidence (%) of Adverse Events Encainide/Placebo Trial Encainide/Quinidine Trial Body System Encainide (N = 88) Placebo (N = 37) Encainide (N = 153) Quinidine (N = 154) Body as a Whole abdominal pain 2.3 0 1.3 3.9 asthenia 14.8 16.2 6.5 13.6 chest pains 10.2 8.1 8.5 8.4 death 3.4 0 1.3 0 fever – – 0 7.8 headache 5.7 5.4 8.5 15.6 lower extremity pain 5.7 0 4.6 5.2 malaise – – 0 3.9 upper extremity pain 4.5 5.4 2.0 3.9 Cardiovascular palpitations 12.5 18.9 7.2 5.8 peripheral edema 2.3 0 1.3 3.2 proarrhythmia 3.4 0 0.7 0.6 Digestive constipation 2.2 0 4.6 2.6 diarrhea 0 8.1 9.2 39.0 dry mouth – – 3.9 2.6 dyspepsia 5.7 5.4 4.6 9.7 nausea 2.3 2.7 8.5 10.4 vomiting 2.3 0 0.7 3.2 Nervous anorexia 1.1 0 2.0 3.2 dizziness 15.9 10.8 15.7 14.9 insomnia 3.4 0 2.0 1.3 nervousness 1.1 0 2.0 3.2 somnolence – – 3.9 1.9 Respiratory dyspnea 8.0 10.8 3.9 8.4 Skin and Appendages rash 1.1 0 2.0 4.5 Special Senses abnormal/blurred vision 3.4 2.7 11.1 5.8 tinnitus – – 3.9 3.9 The following table gives the incidence of the most common adverse events at selected doses of ENKAID that were used during the premarketing clinical trials which involved a total of 749 patients with ventricular arrythmias. The incidence figures in the “0 mg” column are based on events that occurred while patients were on placebo or in drug-free wash out periods. Incidence (%) of the Most Common Adverse Events at Various Doses (Includes all adverse events regardless of relationship to drug therapy.) Daily Doses Body System 0 mg (N = 479) 75 mg (N = 298) 150 mg (N = 260) > 200 mg (N = 208) Body as a Whole abdominal pain 1 2 2 3 asthenia 4 4 5 9 chest pain 3 5 2 6 headache 6 3 5 12 lower extremity pain 3 < 1 1 3 upper extremity pain 1 < 1 < 1 2 pain < 1 < 1 < 1 < 1 paresthesia < 1 1 < 1 2 Cardiovascular congestive heart failure < 1 < 1 1 2 palpitations 5 4 3 8 premature ventricular contraction < 1 < 1 < 1 3 QRS interval prolonged ≥ 0.20 < 1 < 1 3 4 syncope < 1 < 1 1 5 ventricular tachycardia < 1 3 3 8 Digestive constipation 1 < 1 < 1 2 diarrhea 2 < 1 < 1 2 dyspepsia 1 < 1 < 1 3 nausea 2 2 2 6 Nervous dizziness 7 6 10 18 tremor < 1 < 1 < 1 2 Respiratory dyspnea 2 2 5 4 increased cough < 1 < 1 1 2 Skin and Appendages rash 2 < 1 < 1 4 Special Senses abnormal/blurred vision 5 4 8 26 taste perversion < 1 1 2 1 Other adverse events occurring in less than 1% of the patients receiving ENKAID include: malaise, decreased or increased blood pressure, confusion, ataxia, abnormal gait, abnormal sensation, abnormal dreams, diplopia, photophobia and periorbital edema. POSTINTRODUCTION CLINICAL EXPERIENCE Other than the clinical experience in the CAST study described above (see boxed WARNINGS and ADVERSE REACTIONS ), postmarketing experience has shown an adverse experience profile similar to that described for the premarketing clinical trials. Voluntary reports since introduction include rare reports (less than one report per 10,000 patients) of arthralgia, fever, leukopenia, positive ANA test, and thrombocytopenia. Because of the uncontrolled nature of these voluntary reports, and because most of the patients were receiving concomitant medications, any causal relationship to ENKAID treatment is difficult to establish.