TAMBOCOR (flecainide) was included in the National Heart Lung
and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a longterm, multicenter, 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 non-fatal cardiac arrest rate was seen in
patients treated with TAMBOCOR (flecainide) compared with that seen in patients assigned to a carefully matched placebo-treated group. This
rate was 16/315 (5.1%) for TAMBOCOR (flecainide) and 7/309 (2.3%) for the matched placebo. The average duration of treatment with
TAMBOCOR (flecainide) 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
IC agents (including TAMBOCOR (flecainide) ), 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.
Ventricular Pro-arrhythmic Effects in Patients with Atrial
A review of the world literature revealed reports of 568 patients treated with oral TAMBOCOR (flecainide) for
paroxysmal atrial fibrillation/flutter (PAF). Ventricular tachycardia was experienced in 0.4% (2/568) of these
patients. Of 19 patients in the literature with chronic atrial fibrillation (CAF), 10.5% (2) experienced VT or VF. FLECAINIDE IS NOT
RECOMMENDED FOR USE IN PATIENTS WITH CHRONIC ATRIAL FIBRILLATION. Case reports of ventricular
proarrhythmic effects in patients treated with TAMBOCOR (flecainide) for atrial fibrillation/flutter have included
increased PVCs, VT, ventricular fibrillation (VF), and death. As with other Class I agents, patients treated with TAMBOCOR (flecainide)
for atrial flutter have been reported with 1:1 atrioventricular conduction due to slowing the atrial rate. A paradoxical
increase in the ventricular rate also may occur in patients with atrial fibrillation who receive TAMBOCOR (flecainide) . Concomitant negative
chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.
TAMBOCOR (flecainide) , like other antiarrhythmic agents, can cause new or
worsened supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in
frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or
more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of ventricular arrhythmia patients
treated with TAMBOCOR (flecainide) , three-fourths of proarrhythmic events were new or worsened ventricular tachyarrhythmias,
the remainder being increased frequency of PVCs or new supraventricular arrhythmias. In patients treated with
flecainide forsustainedventricular tachycardia, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of
therapy. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were 9 (4%) proarrhythmic events, 8 of them in patients with
paroxysmal atrial fibrillation. Of the 9, 7 (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias
(longer duration, more rapid rate, harder to reverse) while 2 were ventricular arrhythmias, including one fatal case of
VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in
patients with paroxysmal atrial fibrillation and known coronary artery disease.
It is uncertain if TAMBOCOR (flecainide) 's risk of proarrhythmia is
exaggerated in patients with chronic atrial fibrillation (CAF), high ventricular rate, and/or exercise. Wide complex tachycardia
and ventricular fibrillation have been reported in two of 12 CAF patients undergoing maximal exercise tolerance testing.
In patients with complex ventricular arrhythmias, it is
often difficult to distinguish a spontaneous variation in the patient's underlying rhythm disorder from drug-induced worsening, so
that the following occurrence rates must be considered approximations. Their frequency appears to be related to
dose and to the underlying cardiac disease.
Among patients treated forsustainedVT (who frequently also had CHF, a low
ejection fraction, a history of myocardial infarction and/or an episode of cardiac
arrest), the incidence of proarrhythmic events was 13% when dosage was initiated
at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most
patients. In early studies in patients withsustainedVT utilizing a higher initial
dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in
about 10% of the patients treated proarrhythmic events resulted in death, despite
prompt medical attention. With lower initial doses, the incidence of proarrhythmic
events resulting in death decreased to 0.5% of these patients. Accordingly,
it is extremely important to follow the recommended dosage schedule. (See DOSAGE
The relatively high frequency of proarrhythmic events in patients withsustainedVT
and serious underlying heart disease, and the need for careful titration and
monitoring, requires that therapy of patients withsustainedVT be started in
the hospital. (See DOSAGE AND ADMINISTRATION.)
TAMBOCOR (flecainide) has a negative inotropic effect and may cause or worsen CHF, particularly
in patients with cardiomyopathy, preexisting severe heart failure (NYHA functional
class III or IV) or low ejection fractions (less than 30%). In patients with
supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of
patients. In patients withsustainedventricular tachycardia during a mean duration
of 7.9 months of TAMBOCOR (flecainide) therapy, 6.3% (20/317) developed new CHF. In patients
withsustainedventricular tachycardia and a history of CHF, during a mean duration
of 5.4 months of TAMBOCOR (flecainide) therapy, 25.7% (78/304) developed worsened CHF. Exacerbation
of preexisting CHF occurred more commonly in studies which included patients
with class III or IV failure than in studies which excluded such patients. TAMBOCOR (flecainide)
should be used cautiously in patients who are known to have a history of CHF
or myocardial dysfunction. The initial dosage in such patients should be no
more than 100 mg bid (see DOSAGE AND ADMINISTRATION)
and patients should be monitored carefully. Close attention must be given to
maintenance of cardiac function, including optimization of digitalis, diuretic,
or other therapy. In cases where CHF has developed or worsened during treatment
with TAMBOCOR (flecainide) , the time of onset has ranged from a few hours to several months
after starting therapy. Some patients who develop evidence of reduced myocardial
function while on TAMBOCOR (flecainide) can continue on TAMBOCOR (flecainide) with adjustment of digitalis
or diuretics, others may require dosage reduction or discontinuation of TAMBOCOR (flecainide) .
When feasible, it is recommended that plasma flecainide levels be monitored.
Attempts should be made to keep trough plasma levels below 0.7 to 1.0 μg/mL.
Effects on Cardiac Conduction
TAMBOCOR (flecainide) slows cardiac
conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. PR interval increases on average
about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new
first-degree AV heart block (PR interval Â³0.20 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as
150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of
patients developed new bundle branch block while on TAMBOCOR (flecainide) . The degree of lengthening of PR and QRS intervals does not
predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase
to 0.30 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals
occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to
widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation
occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with TAMBOCOR (flecainide) therapy.
Clinically significant conduction changes have been observed
at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second-degree AV block
(0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in
an effort to minimize these effects. (See DOSAGE AND ADMINISTRATION) If second- or third-degree AV block, or right bundle branch
block associated with a left hemiblock occur, TAMBOCOR (flecainide) therapy should be discontinued unless a temporary or implanted ventricular
pacemaker is in place to ensure an adequate ventricular rate.
Sick Sinus Syndrome (Bradycardia-Tachycardia Syndrome)
should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus
bradycardia, sinus pause, or sinus arrest.
Effects on Pacemaker Thresholds
TAMBOCOR (flecainide) is known to
increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if
flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and
should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is
The pacing threshold in patients with pacemakers should be
determined prior to instituting therapy with TAMBOCOR (flecainide) , again after one week of administration and at regular intervals
thereafter. Generally threshold changes are within the range of
multiprogrammable pacemakers and, when these occur, a doubling of either
voltage or pulse width is usually sufficient to regain capture.
Hypokalemia or hyperkalemia may
alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before
administration of TAMBOCOR (flecainide) .
The safety and efficacy of TAMBOCOR (flecainide) in the
fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials. The proarrhythmic
effects of TAMBOCOR (flecainide) , as described previously, apply also to children. In pediatric patients with structural heart disease, TAMBOCOR (flecainide)
has been associated with cardiac arrest and sudden death. TAMBOCOR (flecainide) should be started in the hospital with rhythm monitoring.
Any use of TAMBOCOR (flecainide) in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in