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
Betapace Warnings, Precautions, Pregnancy, Nursing, Abuse - Sotalol
Betapace Warnings, Precautions, Pregnancy, Nursing, Abuse - Sotalol
WARNINGS
Mortality
The National Heart, Lung, and Blood Institute's Cardiac Arrhythmia
Suppression Trial I (CAST I) was a long-term, multi-center, double-blind
study in patients with asymptomatic,
non-life-threatening ventricular arrhythmias, 1 to 103 weeks after
acute myocardial
infarction. Patients in CAST I were randomized to receive placebo
or individually optimized doses of encainide, flecainide, or moricizine.
The Cardiac Arrhythmia Suppression Trial II (CAST II) was similar,
except that the recruited patients had had their index
infarction 4 to 90
days before randomization, patients with left
ventricular ejection
fractions greater than 40% were not admitted, and the randomized
regimens were limited to placebo
and moricizine.
CAST I was discontinued after an average
time-on-treatment of 10 months, and CAST II was discontinued after
an average time-on-treatment
of 18 months. As compared to placebo
treatment, all three
active therapies were associated with increases in short-term (14-day)
mortality, and encainide
and flecainide were associated with significant
increases in longer-term mortality
as well. The longer-term mortality
rate associated with moricizine
treatment could not be statistically distinguished from that associated
with placebo.
The applicability of these results to other populations (e.g., those
without recent myocardial
infarction) and to other than Class I antiarrhythmic agents is uncertain.
BETAPACE® (sotalolhydrochloride) is devoid of Class I effects,
and in a large (n=1,456) controlled trial in patients with a recent
myocardial infarction,
who did not necessarily have ventricular arrhythmias, BETAPACE®
did not produce increased mortality
at doses up to 320 mg/day (see Clinical
Actions). On the other hand, in the large post-infarction
study using a non-titrated initial dose
of 320 mg once daily and
in a second small randomized trial in high-risk post-infarction
patients treated with high doses (320 mg
BID), there have been suggestions of an excess of early sudden deaths.
Proarrhythmia
Like other antiarrhythmic agents, BETAPACE® can provoke new
or worsened ventricular
arrhythmias in some patients, including sustained ventricular
tachycardia or ventricular
fibrillation, with potentially fatal
consequences. Because of its effect on cardiac
repolarization
(QTc interval prolongation),
torsade de pointes, a polymorphic
ventricular tachycardia
with prolongation of the QT interval and a shifting electrical axis
is the most common form
of proarrhythmia associated with BETAPACE®, occurring in about
4% of high risk (history
of sustained VT/VF) patients. The risk
of torsade de pointes progressively increases with prolongation
of the QT interval,
and is worsened also by reduction in heart
rate and reduction
in serum potassium. (See
Electrolyte Disturbances.)
Because of the variable
temporal recurrence
of arrhythmias, it is not always possible to distinguish between
a new or aggravated arrhythmic event and the patient`s underlying
rhythm disorder. (Note,
however, that torsade de pointes is usually a drug-induced arrhythmia
in people with an initially normal QTc.) Thus, the incidence
of drug-related events cannot be precisely determined, so that the
occurrence rates provided must be considered approximations. Note
also that drug-induced arrhythmias may often not be identified,
particularly if they occur long after starting the drug,
due to less frequent monitoring. It is clear from the NIH-sponsored
CAST (see WARNINGS
: Mortality)
that some antiarrhythmic
drugs can cause increased
sudden death mortality,
presumably due to new arrhythmias or asystole, that do not appear
early in treatment
but that represent a sustained increased risk.
Overall in clinical
trials with sotalol, 4.3% of 3257 patients experienced a new or
worsened ventricular
arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular
tachycardia in approximately
1% of patients and torsade de pointes in 2.4%. Additionally, in
approximately 1% of patients, deaths were considered possibly drug-related;
such cases, although difficult
to evaluate, may have been associated with proarrhythmic events.
In patients with a history
of sustained ventricular
tachycardia, the
incidence of torsade de pointes was 4% and worsened VT in about
1%; in patients with other, less serious, ventricular
arrhythmias and supra-ventricular arrhythmias, the incidence
of torsade de pointes was 1% and 1.4%, respectively.
Torsade de pointes arrhythmias were dose
related, as is the prolongation of QT(QTc) interval,
as shown in the table
below.
In addition to dose
and presence of sustained VT, other risk
factors for torsade de pointes were gender
(females had a higher incidence), excessive prolongation of the
QTc interval
(see table below) and
history of cardiomegaly
or congestive heart failure.
Patients with sustained ventricular
tachycardia and a history
of congestive heart failure
appear to have the highest risk for serious proarrhythmia
(7%). Of the patients experiencing torsade de pointes, approximately
two-thirds spontaneously reverted to their baseline rhythm. The
others were either converted electrically (D/C cardioversion or
overdrive pacing) or treated with other drugs (see OVERDOSAGE).
It is not possible to determine whether some sudden deaths represented
episodes of torsade de pointes, but in some instances sudden death
did follow a documented episode
of torsade de pointes. Although BETAPACE® therapy was discontinued
in most patients experiencing torsade de pointes, 17% were continued
on a lower dose. Nonetheless, BETAPACE® should be used with
particular caution if the QTc
is greater than 500 msec
on-therapy and serious consideration should be given to reducing
the dose or discontinuing
therapy when the QTc exceeds
550 msec. Due to the multiple
risk-factors associated with torsade de pointes, however, caution
should be exercised regardless of the QTc
interval. The table below
relates the incidence
of torsade de pointes to on-therapy QTc
and change in QTc from baseline.
It should be noted, however, that the highest on-therapy QTc
was in many cases the one obtained at the time
of the torsade de pointes event, so that the table overstates the
predictive value of a
high QTc .
Proarrhythmic events must be anticipated not only on initiating
therapy, but with every upward dose
adjustment. Proarrhythmic events most often occur within 7 days
of initiating therapy
or of an increase in dose; 75% of serious proarrhythmias (torsade
de pointes and worsened VT) occurred within 7 days of initiating
BETAPACE® therapy,
while 60% of such events
occurred within 3 days of initiation or a dosage
change. Initiating therapy at 80 mg
BID with gradual upward dose
titration and appropriate
evaluations for efficacy
(e.g., PESor Holter) and safety (e.g., QT interval,
heart rate and electrolytes) prior to dose
escalation, should reduce
the risk of proarrhythmia. Avoiding excessive accumulation of sotalolin
patients with diminished renal
function, by appropriate
dose reduction, should
also reduce the risk of
proarrhythmia
(see DOSAGE AND ADMINISTRATION).
Congestive Heart Failure
Sympathetic stimulation is necessary in supporting circulatory
function in congestive
heart failure, and beta-blockade carries the potential
hazard of further depressing myocardial
contractility
and precipitating more severe failure. In patients who have congestive
heart failure
controlled by digitalis
and/or diuretics, BETAPACE® should be administered cautiously.
Both digitalis and sotalolslow AV conduction. As
with all beta-blockers, caution is advised when initiating therapy
in patients with any evidence
of left ventricular dysfunction.
In premarketing studies,
new or worsened congestive heart failure (CHF) occurred in 3.3%
(n=3257) of patients and led to discontinuation in approximately
1% of patients receiving BETAPACE®. The incidence was higher
in patients presenting with sustained ventricular
tachycardia/fibrillation (4.6%, n=1363), or a prior history
of heart failure
(7.3%, n=696). Based on a life-table analysis, the one-year incidence
of new or worsened CHF was 3% in patients without a prior history
and 10% in patients with a prior history of CHF. NYHA Classification
was also closely associated to the incidence of new or worsened
heart failure
while receiving BETAPACE® (1.8% in 1395 Class I patients, 4.9%
in 1254 Class II patients and 6.1% in 278 Class III or IV
patients).
Electrolyte Disturbances
BETAPACE® should not be used in patients with hypokalemia
or hypomagnesemia
prior to correction
of imbalance, as these conditions can exaggerate the degree of QT
prolongation, and increase the potential
for torsade de pointes. Special attention
should be given to electrolyte
and acid-base balance in patients experiencing severe or prolonged
diarrhea or patients
receiving concomitant diuretic
drugs.
Conduction Disturbances
Excessive prolongation of the QT interval (>550 msec) can promote
serious arrhythmias and should be avoided (see Proarrhythmias
above). Sinus bradycardia
(heart rate less than 50
bpm) occurred in 13% of patients receiving BETAPACE® in clinical
trials, and led to discontinuation in about 3% of patients. Bradycardia
itself increases the risk
of torsade de pointes. Sinus pause, sinus
arrest and sinus
node dysfunction
occur in less than 1% of patients. The incidence
of 2nd- or 3rd-degree AV block is approximately 1%.
Recent Acute MI
BETAPACE® can be used safely and effectively in the long-term
treatment of life-threatening
ventricular arrhythmias
following a myocardial
infarction. However, experience
in the use of BETAPACE® to treat cardiac
arrhythmias in the early phase
of recovery from acute
MI is limited and at least at high initial
doses is not reassuring. (See WARNINGS
:
Mortality.) In the first
2 weeks post-MI caution is advised and careful dose
titration is especially
important, particularly in patients with markedly impaired ventricular
function.
The following warnings are related to the beta-blocking activity
of BETAPACE®.
Abrupt Withdrawal
Hypersensitivity to catecholamines has been observed in patients
withdrawn from beta-blocker therapy. Occasional cases of exacerbation
of angina pectoris, arrhythmias
and in some cases, myocardial
infarction have been reported after abrupt discontinuation of beta-blocker
therapy. Therefore, it is prudent when discontinuing chronically
administered BETAPACE®, particularly in patients with ischemic
heart disease,
to carefully monitor the patient
and consider the temporary use of an alternate beta-blocker if appropriate.
If possible, the dosage
of BETAPACE® should be gradually reduced over a period
of one to two weeks. If angina
or acute coronary insufficiency
develops, appropriate
therapy should be instituted
promptly. Patients should be warned against interruption or discontinuation
of therapy without the physician's advice. Because coronary
artery disease
is common and may be unrecognized in patients receiving BETAPACE®,
abrupt discontinuation in patients with arrhythmias may unmask latent
coronary insufficiency.
Non-Allergic Bronchospasm (e.g., chronic
bronchitis and emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT
RECEIVE BETA-BLOCKERS. It is prudent, if BETAPACE® (sotalolhydrochloride)
is to be administered, to use the smallest effective dose, so that
inhibition of bronchodilation produced by endogenous
or exogenous catecholamine
stimulation of beta2 receptors may
be minimized.
Anaphylaxis
While taking beta-blockers, patients with a history of anaphylactic
reaction to a variety
of allergens may have a more severe reaction on repeated challenge,
either accidental, diagnostic
or therapeutic. Such patients may be unresponsive to the usual doses
of epinephrine used
to treat the allergic
reaction.
Anesthesia
The management of patients undergoing major surgery who are being
treated with beta-blockers is controversial. Protracted severe hypotension
and difficulty in restoring and maintaining normal
cardiac rhythm after anesthesia
have been reported in patients receiving beta-blockers.
Diabetes
In patients with diabetes
(especially labile diabetes)
or with a history of
episodes of spontaneous
hypoglycemia, BETAPACE®
should be given with caution since beta-blockade may mask
some important premonitory signs of acute
hypoglycemia; e.g., tachycardia.
Sick Sinus Syndrome
BETAPACE® should be used only with extreme caution in patients
with such sinus
syndrome associated
with symptomatic arrhythmias, because it may cause
sinus bradycardia,
sinus pauses or sinus
arrest.
Thyrotoxicosis
Beta-blockade may mask
certain clinical signs
(e.g., tachycardia) of hyperthyroidism. Patients suspected of developing
thyrotoxicosis should be managed carefully to avoid abrupt withdrawal
of beta-blockade which might be followed by an exacerbation
of symptoms of hyperthyroidism, including thyroid
storm.
PRECAUTIONS
RENAL IMPAIRMENT: BETAPACE® (sotalolhydrochloride) is mainly
eliminated via the kidneys
through glomerular
filtration and to
a small degree by tubular
secretion. There is a direct relationship between renal function,
as measured by serum creatinine
or creatinine clearance,
and the elimination
rate of BETAPACE®.
Guidance for dosing in conditions of renal
impairment can be
found under "DOSAGE AND ADMINISTRATION".
Drug Interactions
See DRUG INTERACTIONS section.
DRUG/Laboratory Test Interactions
The presence of sotalolin the urine
may result in falsely elevated levels of urinary
metanephrine when
measured by fluorimetric or photometric methods. In screening patients
suspected of having a pheochromocytoma
and being treated with sotalol, a specific
method, such as a high
performance liquid
chromatographic assay
with solid phase
extraction (e.g.,
J. Chromatogr. 385:241, 1987) should be employed in determining
levels of catecholamines.
Carcinogenesis, Mutagenicity, Impairment of Fertility
No evidence
of carcinogenic
potential was observed
in rats during a 24-month study at 137-275 mg/kg/day (approximately
30 times the maximum recommended human
oral dose
(MRHD) as mg/kg or 5 times the MRHD as mg/m2)
or in mice, during a 24-month study at 4141-7122 mg/kg/ day (approximately
450-750 times the MRHD as mg/kg or 36-63 times the MRHD as mg/m2).
Sotalol has not been evaluated in any specific
assay of mutagenicity
or clastogenicity.
No significant reduction
in fertility occurred
in rats at oral doses of
1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times
the MRHDas mg/m2 ) prior to mating,
except for a small reduction
in the number of offspring
per litter.
Pregnancy Category B
Reproduction studies in rats and rabbits during organogenesis at
100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m2),
respectively, did not reveal any teratogenic
potential associated
with sotalolHCl. In rabbits,
a high dose of sotalolHCl (160 mg/kg/day) at 16 times the MRHD as
mg/kg (6 times the MRHD as mg/m2)
produced a slight increase in fetal
death likely due to maternal
toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times
the MRHD as mg/m2 ) did not result
in an increased incidence
of fetal deaths. In
rats, 1000 mg/kg/day sotalolHCl, 100 times the MRHD (18 times the
MRHDas mg/m2 ), increased the number
of early resorptions, while at 14 times the maximum dose (2.5 times
the MRHD as mg/m2), no increase
in early resorptions was noted. However, animal
reproduction studies
are not always predictive of human
response.
Although there are no adequate
and well-controlled studies in pregnant women, sotalolHCl has been
shown to cross the placenta,
and is found in amniotic fluid. There has been a report
of subnormal birth
weight with BETAPACE®.
Therefore, BETAPACE® should be used during pregnancy only if
the potential benefit
outweighs the potential
risk.
Nursing Mothers
Sotalol is excreted in the milk
of laboratory animals
and has been reported to be present
in human milk. Because
of the potential for adverse reactions in nursing
infants from BETAPACE®, 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 BETAPACE® in children have not been established.
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