| WARNINGS
Mortality . TAMBOCOR was included in the National Heart
Lung and Blood Institute's Cardiac Arrhythmia Suppression
Trial (CAST), a long-term, 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 compared with
that seen in patients assigned to a carefully matched
placebo-treated group. This rate was 16/315 (5.1%) for
TAMBOCOR and 7/309 (2.3%) for the matched placebo. The
average duration of treatment with TAMBOCOR 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), 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
Fibrillation/Flutter . A review of the world literature
revealed reports of 568 patients treated with oral TAMBOCOR
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 for atrial fibrillation/flutter
have included increased PVCs, VT, ventricular fibrillation
(VF), and death.
As with other Class I agents, patients treated with TAMBOCOR
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. Concomitant
negative chronotropic therapy such as digoxin or beta-blockers
may lower the risk of this complication.
PROARRHYTHMIC EFFECTS
TAMBOCOR, 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, 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 for sustained ventricular 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'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 for sustained VT (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 with sustained VT 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
and Administration .)
The relatively high frequency of proarrhythmic events
in patients with sustained VT and serious underlying heart
disease, and the need for careful titration and monitoring,
requires that therapy of patients with sustained VT be
started in the hospital. (See Dosage and Administration
.)
HEART FAILURE
TAMBOCOR 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
with sustained ventricular tachycardia during a mean duration
of 7.9 months of TAMBOCOR therapy, 6.3% (20/317) developed
new CHF. In patients with sustained ventricular tachycardia
and a history of CHF, during a mean duration of 5.4 months
of TAMBOCOR 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 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,
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
can continue on TAMBOCOR with adjustment of digitalis
or diuretics, others may require dosage reduction or discontinuation
of TAMBOCOR. 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 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 = 0.20 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. 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 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 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).
TAMBOCOR 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 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 available.
The pacing threshold in patients with pacemakers should
be determined prior to instituting therapy with TAMBOCOR,
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.
Electrolyte Disturbances. Hypokalemia or hyperkalemia
may alter the effects of Class I antiarrhythmic drugs.
Preexisting hypokalemia or hyperkalemia should be corrected
before administration of TAMBOCOR.
Pediatric Use. The safety and efficacy of TAMBOCOR in
the fetus, infant, or child have not been established
in double-blind, randomized, placebo-controlled trials.
The proarrhythmic effects of TAMBOCOR, as described previously,
apply also to children. In pediatric patients with structural
heart disease, TAMBOCOR has been associated with cardiac
arrest and sudden death. TAMBOCOR should be started in
the hospital with rhythm monitoring. Any use of TAMBOCOR
in children should be directly supervised by a cardiologist
skilled in the treatment of arrhythmias in children.
PRECAUTIONS
Drug Interactions. TAMBOCOR has been administered to
patients receiving digitalis preparations or beta-adrenergic
blocking agents without adverse effects. During administration
of multiple oral doses of TAMBOCOR to healthy subjects
stabilized on a maintenance dose of digoxin, a 13%-19%
increase in plasma digoxin levels occurred at six hours
postdose.
In a study involving healthy subjects receiving TAMBOCOR
and propranolol concurrently, plasma flecainide levels
were increased about 20% and propranolol levels were increased
about 30% compared to control values. In this formal interaction
study, TAMBOCOR and propranolol were each found to have
negative inotropic effects; when the drugs were administered
together, the effects were additive. The effects of concomitant
administration of TAMBOCOR and propranolol on the PR interval
were less than additive. In TAMBOCOR clinical trials,
patients who were receiving beta blockers concurrently
did not experience an increased incidence of side effects.
Nevertheless, the possibility of additive negative inotropic
effects of beta blockers and flecainide should be recognized.
Flecainide is not extensively bound to plasma proteins.
In vitro studies with several drugs which may be administered
concomitantly showed that the extent of flecainide binding
to human plasma proteins is either unchanged or only slightly
less. Consequently, interactions with other drugs which
are highly protein bound (e.g., anticoagulants ) would
not be expected. TAMBOCOR has been used in a large number
of patients receiving diuretics without apparent interaction.
Limited data in patients receiving known enzyme inducers
( phenytoin, phenobarbital, carbamazepine ) indicate only
a 30% increase in the rate of flecainide elimination.
In healthy subjects receiving cimetidine (1 gm daily)
for one week, plasma flecainide levels increased by about
30% and half-life increased by about 10%.
When amiodarone is added to flecainide therapy, plasma
flecainide levels may increase two-fold or more in some
patients, if flecainide dosage is not reduced. (See Dosage
and Administration .)
Drugs that inhibit cytochrome P450IID6, such as quinidine
, might increase the plasma concentrations of flecainide
in patients that are on chronic flecainide therapy; especially
if these patients are extensive metabolizers.
There has been little experience with the coadministration
of TAMBOCOR and either disopyramide or verapamil. Because
both of these drugs have negative inotropic properties
and the effects of coadministration with TAMBOCOR are
unknown, neither disopyramide nor verapamil should be
administered concurrently with TAMBOCOR unless, in the
judgment of the physician, the benefits of this combination
outweigh the risks. There has been too little experience
with the coadministration of TAMBOCOR with nifedipine
or diltiazem to recommend concomitant use.
Carcinogenesis, Mutagenesis, Impairment of Fertility.
Long-term studies with flecainide in rats and mice at
doses up to 60 mg/kg/day have not revealed any compound-related
carcinogenic effects. Mutagenicity studies (Ames test,
mouse lymphoma and in vivo cytogenetics) did not reveal
any mutagenic effects. A rat reproduction study at doses
up to 50 mg/kg/day (seven times the usual human dose)
did not reveal any adverse effect on male or female fertility.
Pregnancy. Pregnancy Category C. Flecainide
has been shown to have teratogenic effects (club paws,
sternebrae and vertebrae abnormalities, pale hearts with
contracted ventricular septum) and an embryotoxic effect
(increased resorptions) in one breed of rabbit (New Zealand
White) when given doses of 30 and 35 mg/kg/day, but not
in another breed of rabbit (Dutch Belted) when given doses
up to 30 mg/kg/day. No teratogenic effects were observed
in rats and mice given doses up to 50 and 80 mg/kg/day,
respectively; however, delayed sternebral and vertebral
ossification was observed at the high dose in rats. Because
there are no adequate and well-controlled studies in pregnant
women, TAMBOCOR should be used during pregnancy only if
the potential benefit justifies the potential risk to
the fetus.
Labor and Delivery. It is not known
whether the use of TAMBOCOR during labor or delivery has
immediate or delayed adverse effects on the mother or
fetus, affects the duration of labor or delivery, or increases
the possibility of forceps delivery or other obstetrical
intervention.
Nursing Mothers. Results from a multiple
dose study conducted in mothers soon after delivery indicates
that flecainide is excreted in human breast milk in concentrations
as high as 4 times (with average levels about 2.5 times)
corresponsing plasma levels; assuming a maternal plasma
level at the top of the therapeutic range (1 µg/mL),
the calculated daily dose to a nursing infant (assuming
about 700 mL breast milk over 24 hours) would be less
than 3 mg.
Pediatric Use. The safety and efficacy
of TAMBOCOR in the fetus, infant, or child have not been
established in double-blind, randomized, placebo-controlled
trials (see CLINICAL PHARMACOLOGY,
WARNINGS , and DOSAGE AND ADMINISTRATION).
Hepatic Impairment. Since flecainide
elimination from plasma can be markedly slower in patients
with significant hepatic impairment, TAMBOCOR should not
be used in such patients unless the potential benefits
clearly outweigh the risks. If used, frequent and early
plasma level monitoring is required to guide dosage (see
Plasma Level Monitoring); dosage increases should be made
very cautiously when plasma levels have plateaued (after
more than four days).
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