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* |
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| Total Daily Dose (mg) |
|---|
| | 75 | | 150 | | 200 |
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| 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.
PRECAUTIONS
Drug Interactions
In prospective studies single and multiple doses of ENKAID have had no significant effect on serum digoxin levels. Likewise, combined digoxin/ENKAID therapy has been administered without adverse effects.
Experience has indicated no obvious problems with the combined use of ENKAID and other antiarrhythmic agents, diuretics, beta blockers or calcium channel blockers. However, because of possible additive pharmacologic effects, caution is indicated when ENKAID is used with another antiarrhythmic agent or any other drug that affects cardiac conduction.
Cimetidine (300 mg q.i.d.) increases plasma concentrations of encainide and its active metabolites. Although no clinically significant consequences have been reported, caution should be utilized when the two drugs are administered simultaneously. ENKAID dosage should be reduced if cimetidine is to be given to a patient taking ENKAID.
In vitro binding studies with several drugs that may be administered concomitantly have not revealed any significant alteration in the protein binding of encainide, ODE, or MODE; nor did high concentrations of encainide and its metabolites alter the binding of the other medications including such highly protein bound drugs as warfarin.
Hepatic Impairment
Patients with hepatic impairment have a significantly reduced rate of elimination of encainide, probably as a consequence of decreased metabolism to ODE and MODE; serum concentrations of ODE and MODE, however, are little altered. There is insufficient experience to be certain about the need for alterations in the dose and/or dosing interval of ENKAID in patients with hepatic disease, but it is prudent to increase doses cautiously.
Renal Impairment
Limited data suggest that reduction in the elimination of encainide and its active metabolites ODE and MODE in patients with severe renal impairment (serum creatinine > 3.5 mg/dL or creatinine clearance of less than 20 mL/min) results in significant accumulation of metabolites and, to a lesser degree, encainide. In such patients, therapy with ENKAID should be initiated with a single daily dose of 25 mg. If needed the dose may be increased to 25 mg b.i.d. after at least 7 days, and again to 25 mg t.i.d. after an additional 7 days if necessary. Doses above 150 mg per day are not recommended. Consideration should be given to reducing ENKAID dosage if renal function deteriorates significantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have been performed by the oral route in rats and mice at doses up to 30 mg/kg/day and 135 mg/kg/day, respectively. No drug-related increase in tumor incidence was observed. Bacterial and mammalian mutagenicity tests with encainide have been negative. No reduction in fertility occurred in rats at oral doses up to 14 mg/kg/day. Fertility was reduced when both male and female rats received oral doses of 28 mg/kg/day (approximately 13 times the average human dose) prior to mating; there was no reduction with treatment of each sex separately at the same dose.
Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at doses up to 13 and 9 times the average human dose, respectively, and have revealed no evidence of harm to the fetus due to encainide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Encainide is excreted in the milk of laboratory animals and has been reported to be present in human milk. Although no overt postnatal effects were observed in the postnatal phase of the rodent reproduction studies, other than decreased weight at the highest dose of 28 mg/kg/day (13 times human dose), the potential for serious adverse reactions in nursing infants from ENKAID is unknown. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of ENKAID (encainide hydrochloride) in pediatric patients have not been established.
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