A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rythmol Warnings, Precautions, Pregnancy, Nursing, Abuse - Propafenone
Rythmol Warnings, Precautions, Pregnancy, Nursing, Abuse - Propafenone
WARNINGS
| Mortality
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
nonlife-threatening ventricular
arrhythmias who had a myocardial
infarction
more than six days but less than two years previously, an
increased rate
of death or reversed
cardiac arrest
(7.7%; 56/ 730) was seen in patients treated with encainide
or flecainide (class 1C antiarrhythmics) compared with that
seen in patients assigned to placebo (3.0%; 22/ 725). The
average duration
of treatment
with encainide or flecainide in this study was ten months.
The applicability of the CAST results to other populations
(e.g., those without recent myocardial
infarction) or other antiarrhythmic
drugs is uncertain, but at present
it is prudent to consider any 1C antiarrhythmic to have
a significant
risk in patients
with structural
heart disease.
Given the lack of any evidence
that these drugs improve survival, antiarrhythmic agents
should generally be avoided in patients with non-life-threatening
ventricular arrhythmias, even if the patients are experiencing
unpleasant, but not life-threatening, symptoms or signs.
|
Proarrhythmic Effects
RYTHMOL (propafenone HCl), like other antiarrhythmic
agents, may cause new or worsened arrhythmias. Such proarrhythmic
effects range from an
increase in frequency
of PVCs to the development
of more severe ventricular
tachycardia, ventricular fibrillation
or torsade de pointes; i.e., tachycardia
that is more sustained or more rapid which may lead
to fatal consequences.
It is therefore essential
that each patient given
RYTHMOL be evaluated electrocardiographically and clinically prior
to, and during therapy
to determine whether the response to RYTHMOL supports continued
treatment.
Overall in clinical
trials with propafenone, 4.7% of all patients had new or worsened
ventricular arrhythmia
possibly representing a pro-arrhythmic event (0.7% was an increase
in PVCs; 4.0% a worsening, or new appearance, of VT or VF). Of the
patients who had worsening of VT (4%), 92% had a history of VT and
or VT/ yE, 71% had coronary
artery disease,
and 68% had a prior myocardial infarction. The incidence
of proarrhythmia
in patients with less serious or benign
arrhythmias, which include patients with an increase in frequency
of PVCs, was 1.6%. Although most proarrhythmic events occurred during
the first week of therapy,
late events also were seen and the CAST study (see Mortality
above) suggests that an increased risk
is present throughout treatment.
In the 474 patient
U.S. multicenter trial in patients with symptomatic SVT, 1 .9% (9/
474) of these patients experienced ventricular
tachycardia (VT) or ventricular
fibrillation (VF)
during the study. However, in 4 of the 9 patients, the ventricular
tachycardia was
of atrial origin. Six
of the nine patients that developed ventricular
arrhythmias did so within 14 days of onset of therapy. About 2.3%
(11/ 474) of all patients had a recurrence of SVT during the study
which could have been a change in the patients’ arrhythmia
behavior or could represent
a proarrhythmic event. Case reports in patients treated with RYTHMOL
for atrial fibrillation/
flutter have included increased PVCs, VT, VF, and death.
Nonallergic Bronchospasm (e. g., chronic
bronchitis, emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE
PROPAFENONE or other agents with beta-adrenergic-blocking activity.
Congestive Heart Failure
During treatment
with oral propafenone in
patients with depressed
baseline function (mean EF= 33.5%), no
significant decreases
in ejection fraction
were seen. In clinical
trial experience, new or worsened CHF
has been reported in 3.7% of patients with ventricular
arrhythmia; of those 0.9% were considered probably or definitely
related to RYTHMOL. Of the patients with congestive heart failure
probably related to propafenone, 80% had pre-existing heart failure
and 85% had coronary
artery disease. CHF
attributable to RYTHMOL developed rarely (< 0.2%) in ventricular
arrhythmia patients
who had no previous history
of CHF. CHF occurred in
1.9% of patients studied with PAF or PSVT.
As RYTHMOL exerts both beta
blockade and a (dose-related)
negative inotropic
effect on cardiac muscle,
patients with congestive heart
failure should be fully
compensated before receiving RYTHMOL. If congestive heart
failure worsens, RYTHMOL should be discontinued (unless congestive
heart failure is due to
the cardiac arrhythmia)
and if indicated, restarted
at a lower dosage only after adequate cardiac
compensation has
been established.
Conduction Disturbances
RYTHMOL slows atrioventricular
conduction and also
causes first degree AV block. Average PR interval
prolongation and increases in QRS duration are closely correlated
with dosage increases
and concomitant
increases in propafenone plasma
concentrations. The incidence
of first degree, second
degree, and third degree
AV block observed in 2,127
patients was 2.5%, 0.6%, and 0.2%, respectively. Development of
second or third degree
AV block requires a reduction
in dosage or discontinuation
of RYTHMOL. Bundle branch block
(1.2%) and intraventricular
conduction delay
(1.1 %) have been reported in patients receiving propafenone. Bradycardia
has also been reported (1.5%). Experience in patients with such
sinus node
syndrome is limited
and these patients should not be treated with propafenone.
Effects on Pacemaker Threshold
RYTHMOL may alter both pacing
and sensing thresholds of artificial
pacemakers. Pacemakers should be monitored and programmed accordingly
during therapy.
Hematologic Disturbances
Agranulocytosis (fever, chills, weakness, and neutropenia) has
been reported in patients receiving propafenone. Generally, the
agranulocytosis occurred within the first two months of propafenone
therapy and upon discontinuation
of therapy, the white
count usually normalized
by 14 days. Unexplained fever and/or decrease in white
cell count, particularly
during the initial three months of therapy,
warrant consideration of possible agranulocytosis/ granulocytopenia.
Patients should be instructed to promptly report
the development of any signs of infection
such as fever,
sore throat,
or chills.
PRECAUTIONS
Hepatic Dysfunction
Propafenone is highly metabolized by the liver
and should, therefore, be administered cautiously to patients with
impaired hepatic function.
Severe liver dysfunction
increases the bioavailability
of propafenone to approximately 70% compared to 3-40% for patients
with normal liver
function. In eight patients with moderate to severe liver
disease, the mean
half-life was approximately 9 hours. As
a result, the dose of propafenone
given to patients with impaired hepatic
function should be
approximately 20-30% of the dose
given to patients with normal
hepatic function
(see DOSAGE AND ADMINISTRATION).
Careful monitoring for excessive pharmacological effects (see OVERDOSAGE)
should be carried out.
Renal Dysfunction
A considerable percentage of propafenone metabolites (18.5%-38%
of the dose/ 48 hours) are excreted in the urine.
Until further data are available, RYTHMOL (propafenone HCl) should
be administered cautiously to patients with impaired renal
function. These patients should be carefully monitored for signs
of overdosage (see OVERDOSAGE).
Elevated ANA Titers
Positive ANA titers have been reported in patients receiving propafenone.
They have been reversible
upon cessation of treatment
and may disappear even in the face
of continued propafenone therapy. These laboratory
findings were usually not associated with clinical
symptoms, but there is one published case of drug-induced lupus
erythematosis (positive rechallenge); it resolved completely upon
discontinuation of therapy. Patients who develop an abnormal ANA
test should be carefully
evaluated and if persistent
or worsening elevation of ANA titers is detected, consideration
should be given to discontinuing therapy.
Impaired Spermatogenesis
Reversible disorders of spermatogenesis
have been demonstrated in monkeys, dogs and rabbits after high dose
intravenous administration.
Evaluation of the effects of short-term propafenone administration
on spermatogenesis in 11 normal
subjects suggests that propafenone produced a reversible, short-term
drop (within normal
range) in sperm count.
Subsequent evaluations in 11 patients receiving propafenone chronically
have suggested no effect
of propafenone on sperm
count.
Neuromuscular Dysfunction
Exacerbation of myasthenia
gravis has been reported during propafenone therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime maximally tolerated oral
dose studies in mice (up
to 360 mg/kg/day) and rats (up to 270 mg/kg/day) provided no
evidence of a carcinogenic
potential for propafenone.
RYTHMOL was not mutagenic when assayed for genotoxicity in 1) mouse
Dominant Lethal test, 2) rat
bone marrow
Chromosome Analysis, 3) Chinese hamster bone
marrow and spermatogonia
chromosome analysis,
4) Chinese hamster micronucleus test, and 5) Ames bacterial test.
Propafenone administered intravenously to rabbits, dogs, and monkeys
has been shown to decrease spermatogenesis. These effects were reversible,
were not found following oral
dosing of propafenone, were seen only at lethal or sublethal
dose levels and were not
seen in rats treated either orally or intravenously (see Impaired
Spermatogenesis, above). Propafenone did not affect
fertility rates when
administered orally to male
and female rats at doses up to 270 mg/kg/day or when administered
orally or intravenously to male
rabbits at doses of 120 mg/kg/day or 3.5 mg/kg/day, respectively.
On a body weight
basis, the above noted oral
doses in rat and rabbit
are 18 times and 8 times, respectively, the maximum
recommended daily human dose of 900 mg
(based on 60kg human body
weight).
Pregnancy
Teratogenic Effects: Pregnancy Category C: Propafenone
has been shown to be embryotoxic in rabbits and rats when given
in doses 10 and 40 times, respectively, the maximum
recommended human dose.
No teratogenic potential
was apparent in either
species. There are no adequate
and well-controlled studies in pregnant
women. Propafenone should be used during pregnancy only if the potential
benefit justifies the
potential risk
to the fetus.
Nonteratogenic Effects: In
a perinatal and postnatal
study in rats, propafenone, at dose
levels of 6 or more times the maximum
recommended human dose, produced dose
dependent increases in maternal
and neonatal mortality, decreased maternal
and pup body weight
gain and reduced neonatal
physiological development.
Labor and Delivery
It is not known whether the use of propafenone during labor
or delivery has immediate
or delayed adverse effects on the fetus,
or whether it prolongs the duration
of labor or increases
the need for forceps
delivery or other obstetrical
intervention.
Nursing Mothers
It is not known whether this drug
is excreted in human milk.
Because many drugs are excreted in human
milk and because of the
potential for serious
adverse reactions in nursing
infants from RYTHMOL, 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 RYTHMOL in pediatric
patients have not been established.
Geriatric Use
There do not appear to be any age-related differences in adverse
reaction rates in the most commonly reported adverse reactions.
Because of the possible increased risk
of impaired hepatic
or renal function
in this age group, RYTHMOL
should be used with caution. The effective dose
may be lower in these patients.
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