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.
PRECAUTIONS
General:
Electrocardiographic Changes/Conduction Abnormalities
Ethmozine® slows AV nodal and intraventricular conduction, producing dose-related increases in the PR and QRS intervals. In clinical trials, the average increase in the PR interval was 12% and the QRS interval was 14%. Although the QTC interval was increased, this is wholly because of QRS prolongation; the JT interval is shortened, indicating the absence of significant slowing of ventricular repolarization. The degree of lengthening of PR and QRS intervals does not predict efficacy.
In controlled clinical trials and in open studies, the overall incidence of delayed ventricular conduction, including new bundle branch block pattern, was approximately 9.4%. In patients without baseline conduction abnormalities, the frequency of second-degree AV block was 0.2% and third-degree AV block did not occur. In patients with baseline conduction abnormalities, the frequencies of second-degree AV block and third-degree AV block were 0.9% and 1.4%, respectively.
Ethmozine® therapy was discontinued in 1.6% of patients due to electrocardiographic changes (0.6% due to sinus pause or asystole, 0.2% to AV block, 0.2% to junctional rhythm, 0.4% to intraventricular conduction delay, and 0.2% to wide QRS and/or PR interval).
In patients with pre-existing conduction abnormalities, Ethmozine® therapy should be initiated cautiously. If second- or third-degree AV block occurs, Ethmozine® therapy should be discontinued unless a ventricular pacemaker is in place. When changing the dose of Ethmozine® or adding concomitant medications which may also affect cardiac conduction, patients should be monitored electrocardiographically.
Hepatic Impairment
Patients with significant liver dysfunction have reduced plasma clearance and an increased half-life of Ethmozine®. Although the precise relationship of Ethmozine® levels to effect is not clear, patients with hepatic disease should be treated with lower doses and closely monitored for excessive pharmacological effects, including effects on ECG intervals, before dosage adjustment. Patients with severe liver disease should be administered Ethmozine® with particular care, if at all (see DOSAGE AND ADMINISTRATION).
Renal Impairment
Plasma levels of intact Ethmozine® are unchanged in hemodialysis patients, but a significant portion (39%) of Ethmozine® is metabolized and excreted in the urine. Although no identified active metabolite is known to increase in people with renal failure, metabolites of unrecognized importance could be affected. For this reason, Ethmozine® should be administered cautiously in patients with impaired renal function. Patients with significant renal dysfunction should be started on lower doses and monitored for excessive pharmacologic effects, including ECG intervals, before dosage adjustment (see DOSAGE AND ADMINISTRATION).
Congestive Heart Failure
Most patients with congestive heart failure have tolerated the recommended Ethmozine® daily doses without unusual toxicity or change in effect. Pharmacokinetic differences between Ethmozine® patients with and without congestive heart failure were not apparent (See Hepatic Impairment above). In some cases, worsened heart failure has been attributed to Ethmozine®. Patients with pre-existing heart failure should be monitored carefully when Ethmozine® is initiated.
Effects on Pacemaker Threshold
The effect of Ethmozine® on the sensing and pacing thresholds of artificial pacemakers has not been sufficiently studied. In such patients, pacing parameters must be monitored, if Ethmozine® is used.
Drug Interactions
No significant changes in serum digoxin levels or pharmacokinetics have been observed in patients or healthy subjects receiving concomitant Ethmozine® therapy. Concomitant use was associated with additive prolongation of the PR interval, but not with a significant increase in the rate of second- or third-degree AV block.
Concomitant administration of cimetidine resulted in a decrease in Ethmozine® clearance of 49% and a 1.4 fold increase in plasma levels in healthy subjects. During clinical trials, no significant changes in the efficacy or tolerance of Ethmozine® have been observed in patients receiving concomitant cimetidine therapy. Patients on cimetidine should have Ethmozine® therapy initiated at relatively low doses, not more than 600 mg/day. Patients should be monitored when concomitant cimetidine therapy is instituted or discontinued or when the Ethmozine® dose is changed.
Concomitant administration of beta blacker therapy did not reveal significant changes in overall electrocardiographic intervals in patients. In one controlled study, Ethmozine® (moricizine hydrochloride) and propranolol administered concomitantly produced a small additive increase in the PR interval.
Theophylline clearance and plasma half-life were significantly affected by multiple dose Ethmozine® administration when both conventional and sustained release theophylline were given to healthy subjects (clearance increased 44-66% and plasma half-life decreased 19-33%). Plasma theophylline levels should be monitored when concomitant Ethmozine® is initiated or discontinued.
Because of possible additive pharmacologic effects, caution is indicated when Ethmozine® is used with any drug that affects cardiac electrophysiology. Uncontrolled experience in patients indicates no serious adverse interaction during the concomitant use of Ethmozine® and diuretics, vasodilators, antihypertensive drugs, calcium channel blockers, beta blockers, angiotensin-converting enzyme inhibitors, or warfarin. Plasma warfarin levels, warfarin pharmacokinetics, and prothrombin times were unaffected during multiple dose Ethmozine® administration to young, healthy, male subjects in a controlled study. However, there are isolated reports of the need to either increase or decrease warfarin doses after initiation of Ethmozine®. Some patients who were taking warfarin with a stable prothrombin time experienced excessive prolongation of the prothrombin time following the initiation of Ethmozine®. In some cases, liver enzymes also were elevated. Bleeding or bruising may occur. When Ethmozine® is started or stopped in a patient stabilized on warfarin, more frequent prothrombin time monitoring is advisable.
Results from in vitro studies do not suggest alterations in Ethmozine® plasma protein binding in the presence of other highly plasma protein bound drugs.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
In a 24-month mouse study in which Ethmozine® was administered in the feed at concentrations calculated to provide doses ranging up to 320 mg/kg/day, ovarian tubular adenomas and granulosa cell tumors were limited in occurrence to Ethmozine® treated animals. Although the findings were of borderline statistical significance, or not statistically significant, historical control data indicate that both of these tumors are uncommon in the strain of mouse studied.
In a 24-month mouse study in which Ethmozine® was administered by gavage to rats at doses of 25, 50 and 100 mg/kg/day, Zymbal's Gland Carcinoma was observed in one mid-dose and two high-dose males. This tumor appears to be uncommon in the strain of rat studied. Rats of both sexes showed a dose-related increase in hepatocellular cholangioma (also described as bile ductile cystadenoma or cystic hyperplasia) along with fatty metamorphosis, possibly due to disruption of hepatic choline utilization for phospholipid biosynthesis. The rat is known to be uniquely sensitive to alteration in choline metabolism.
Ethmozine® was not mutagenic when assayed for genotoxicity in in vitro bacterial (Ames test) and mammalian (Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase and sister chromatid exchange) cell systems or in in vivo mammalian systems (rate bone cytogenicity and mouse micronucleus).
A general reproduction and fertility study was conducted in rats at dose levels up to 6.7 times the maximum recommended human dose of 900 mg/day (based upon 50 kg human body weight) and revealed no evidence of impaired male or female fertility.
Pregnancy
Teratogenic Effects: Pregnancy Category B
Teratology studies have been performed with Ethmozine® in rats and in rabbits at doses up to 6.7 and 4.7 times the maximum recommended human daily dose, respectively, and have revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Ethmozine® should be used during pregnancy only if clearly needed.
Pregnancy-Nonteratogenic Effects:
In a study in which rats were dosed with Ethmozine® prior to mating, during mating and throughout gestation and lactation, dose levels 3.4 and 6.7 times the maximum recommended human daily dose produced a dose-related decrease in pup and maternal weight gain, possibly related to a larger litter size. In a study in which dosing was begun on Day 15 of gestation, Ethmozine®, at a level 6.7 times the maximum recommended human daily dose, produced a retardation in maternal weight gain but no effect on pup growth.
Nursing Mothers
Ethmozine® is secreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for serious adverse reactions in nursing infants from Ethmozine®, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of Ethmozine® in children less than 18 years of age have not been established.
|
