United States - English - NLM (National Library of Medicine)
SOTALOL HYDROCHLORIDE- sotalol hydrochloride tablet
Sotalol Hydrochloride Tablets, USP
To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol
hydrochloride tablets should be placed for a minimum of three days (on their maintenance
dose) in a facility that can provide cardiac resuscitation and continuous
electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing.
For detailed instructions regarding dose selection and special cautions for people with renal
impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the
maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial
flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus
rhythm and is marketed under the brand name Betapace AF
. Sotalol hydrochloride
tablets, USP are not approved for the AFIB/AFL indication and should not be substituted
for Betapace AF because only Betapace AF is distributed with a patient package insert that
is appropriate for patients with AFIB/AFL.
Sotalol hydrochloride tablets, USP are an antiarrhythmic drug with Class II (beta-adrenoreceptor
blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a
white to off-white, capsule-shaped, scored tablet for oral administration. Sotalol hydrochloride is a
white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene
glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-
N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The
molecular formula is C
SHCl and is represented by the following structural formula:
Each tablet, for oral administration, contains 80 mg, 120 mg, 160 mg or 240 mg of sotalol
hydrochloride. In addition, each tablet also contains the following inactive ingredients: magnesium
stearate and microcrystalline cellulose.
Mechanism of Action
Sotalol hydrochloride has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac
action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol
hydrochloride is a racemic mixture of d-and l-sotalol. Both isomers have similar Class III
antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity.
The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and
maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane
stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant
Class III effects are seen only at daily doses of 160 mg and above.
In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m
area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed
at daily doses ≥ 90 mg/m
Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte,
as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact
animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of
atrial and ventricular muscle and conduction tissue.
In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased
sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal
refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and
ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle,
ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde
and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related
mean increases of 40 to 100 msec in QT and 10 to 40 msec in QT
. (See WARNINGS for description
of relationship between QT
and Torsade de Pointes type arrhythmias). No significant alteration in
QRS interval is observed.
In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol, the
average defibrillatory threshold was 6 joules (range 2 to 15 joules) compared to a mean of 16 joules for
a nonrandomized comparative group primarily receiving amiodarone.
Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular
(VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an
ascending titration regimen with daily doses of 30, 90 and 210 mg/m
with dosing every 8 hours for a
total 9 doses. During steady-state, the respective average increases above baseline of the QT
in msec (%), were 2(+1%), 14(+4%) and 29(+7%) msec at the 3 dose levels. The respective mean
maximum increases above baseline of the QT
interval, in msec (%), were 23(+6%), 36(+9%) and
55(+14%) msec at the 3 dose levels. The steadystate percent increases in the RR interval were 3, 9 and
12%. The smallest children (BSA<0.33m
) showed a tendency for larger Class III effects (ΔQT
an increased frequency of prolongations of the QT
interval as compared with larger children
). The beta-blocking effects also tended to be greater in the smaller children
). Both the Class III and beta-blocking effects of sotalol were linearly related with the
In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection
fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg
twice daily of sotalol hydrochloride produced a 28% reduction in heart rate and a 24% decrease in
cardiac index at 2 hours post dosing at steady-state. Concurrently, systemic vascular resistance and
stroke volume showed nonsignificant increases of 25% and 8%, respectively. Pulmonary capillary
wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed
the study. One patient was discontinued because of worsening congestive heart failure. Mean arterial
pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise
and isoproterenol induced tachycardia are antagonized by sotalol, and total peripheral resistance
increases by a small amount.
In hypertensive patients, sotalol hydrochloride produces significant reductions in both systolic and
diastolic blood pressures. Although sotalol hydrochloride is usually well-tolerated hemodynamically,
caution should be exercised in patients with marginal cardiac compensation as deterioration in cardiac
performance may occur. (See WARNINGS, Congestive Heart Failure).
Sotalol hydrochloride has been studied in life-threatening and less severe arrhythmias. In patients with
frequent premature ventricular complexes (VPC), sotalol hydrochloride was significantly superior to
placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the
response was dose-related through 640 mg/day with 80 to 85% of patients having at least a 75%
reduction of VPCs. Sotalol hydrochloride was also superior, at the doses evaluated, to propranolol (40
to 80 mg TID) and similar to quinidine (200 to 400 mg QID) in reducing VPCs. In patients with life-
threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol hydrochloride
was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by
suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.
In a double-blind, randomized comparison of sotalol and procainamide given intravenously (total of 2
mg/kg sotalol vs. 19 mg/kg of procainamide over 90 minutes), sotalol suppressed PES induction in 30%
of patients vs. 20% for procainamide (p=0.2).
In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring
(ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor
selection (in each case followed by treadmill exercise testing) in patients with a history of sustained
VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol
hydrochloride was compared with 6 other drugs (procainamide, quinidine, mexiletine, propafenone,
imipramine and pirmenol). Overall response, limited to first randomized drug, was 39% for sotalol and
30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of
PES induction was 36% for sotalol vs. a mean of 13% for the other drugs. Using the Holter monitoring
endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC
pairs, and at least 70% suppression of VPCs), sotalol yielded 41% response vs. 45% for the other
drugs combined. Among responders placed on long-term therapy identified acutely as effective (by
either PES or Holter), sotalol, when compared to the pool of other drugs, had the lowest two-year
mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest
withdrawal rate (38% vs. about 75 to 80%). The most commonly used doses of sotalol hydrochloride in
this trial were 320 to 480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18%
receiving 640 mg or more.
It cannot be determined, however, in the absence of a controlled comparison of sotalol vs. no
pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol response causes
improved survival or identifies a population with a good prognosis.
In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456), sotalol
hydrochloride was given as a non-titrated initial dose of 320 mg once daily. Sotalol did not produce a
significant increase in survival (7.3% mortality on sotalol vs 8.9% on placebo, p=0.3), but overall did
not suggest an adverse effect on survival. There was, however, a suggestion of an early (i.e., first 10
days) excess mortality (3% on sotalol vs. 2% on placebo). In a second small trial (n=17 randomized to
sotalol) where sotalol was administered at high doses (e.g., 320 mg twice daily) to high-risk post-
infarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4
fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol.
In healthy subjects, the oral bioavailability of sotalol hydrochloride is 90 to 100%. After oral
administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma
concentrations are attained within 2 to 3 days (i.e., after 5 to 6 doses when administered twice daily).
Over the dosage range 160 to 640 mg/day sotalol hydrochloride displays dose proportionality with
respect to plasma concentrations. Distribution occurs to a central (plasma) and to a peripheral
compartment, with a mean elimination half-life of 12 hours. Dosing every 12 hours results in trough
plasma concentrations which are approximately one-half of those at peak.
Sotalol hydrochloride does not bind to plasma proteins and is not metabolized. Sotalol hydrochloride
shows very little intersubject variability in plasma levels. The pharmacokinetics of the d and l
enantiomers of sotalol are essentially identical. Sotalol hydrochloride crosses the blood brain barrier
poorly. Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are
necessary in conditions of renal impairment (see DOSAGE AND ADMINISTRATION). Age per se
does not significantly alter the pharmacokinetics of sotalol hydrochloride, but impaired renal function in
geriatric patients can increase the terminal elimination half-life, resulting in increased drug
accumulation. The absorption of sotalol hydrochloride was reduced by approximately 20% compared
to fasting when it was administered with a standard meal. Since sotalol hydrochloride is not subject to
first-pass metabolism, patients with hepatic impairment show no alteration in clearance of sotalol.
The combined analysis of two unblinded, multicenter trials (a single dose and a multiple dose study)
with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first
order. A daily dose of 30 mg/m
of sotalol was administered in the single dose study and daily doses
of 30, 90 and 210 mg/m
were administered q 8h in the multi-dose study. After rapid absorption with
peak levels occurring on average between 2 to 3 hours following administration, sotalol was eliminated
with a mean half life of 9.5 hours. Steady-state was reached after 1 to 2 days. The average peak to
trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for
the pharmacokinetics of sotalol. The smallest children (BSA<0.33m
) exhibited a greater drug
exposure (+59%) than the larger children who showed a uniform drug concentration profile. The
intersubject variation for oral clearance was 22%.
INDICATIONS AND USAGE
Sotalol hydrochloride tablets, USP are indicated for the treatment of documented ventricular
arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-
threatening. Because of the proarrhythmic effects of sotalol hydrochloride tablets, USP (see
WARNINGS), including a 1.5 to 2% rate of Torsade de Pointes or new VT/VF in patients with either
NSVT or supraventricular arrhythmias, its use in patients with less severe arrhythmias, even if the
patients are symptomatic, is generally not recommended. Treatment of patients with asymptomatic
ventricular premature contractions should be avoided.
Initiation of sotalol hydrochloride treatment or increasing doses, as with other antiarrhythmic agents
used to treat life-threatening arrhythmias, should be carried out in the hospital. The response to
treatment should then be evaluated by a suitable method (e.g., PES or Holter monitoring) prior to
continuing the patient on chronic therapy. Various approaches have been used to determine the response
to antiarrhythmic therapy, including sotalol hydrochloride tablets, USP.
In the ESVEM Trial, response by Holter monitoring was tentatively defined as 100% suppression of
ventricular tachycardia, 90% suppression of non-sustained VT, 80% suppression of paired VPCs, and
75% suppression of total VPCs in patients who had at least 10 VPCs/hour at baseline; this tentative
response was confirmed if VT lasting 5 or more beats was not observed during treadmill exercise
testing using a standard Bruce protocol. The PES protocol utilized a maximum of three extrastimuli at
three pacing cycle lengths and two right ventricular pacing sites. Response by PES was defined as
prevention of induction of the following: 1) monomorphic VT lasting over 15 seconds; 2) non-sustained
polymorphic VT containing more than 15 beats of monomorphic VT in patients with a history of
monomorphic VT; 3) polymorphic VT or VF greater than 15 beats in patients with VF or a history of
aborted sudden death without monomorphic VT; and 4) two episodes of polymorphic VT or VF of
greater than 15 beats in a patient presenting with monomorphic VT. Sustained VT or NSVT producing
hypotension during the final treadmill test was considered a drug failure.
In a multicenter open-label long-term study of sotalol in patients with life-threatening ventricular
arrhythmias which had proven refractory to other antiarrhythmic medications, response by Holter
monitoring was defined as in ESVEM. Response by PES was defined as non-inducibility of sustained
VT by at least double extrastimuli delivered at a pacing cycle length of 400 msec. Overall survival and
arrhythmia recurrence rates in this study were similar to those seen in ESVEM, although there was no
comparative group to allow a definitive assessment of outcome.
Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.
Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial
fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus
rhythm and is marketed under the brand name Betapace AF (sotalol hydrochloride, tablets, USP). Sotalol
hydrochloride tablets, USP are not approved for the AFIB/AFL indication and should not be substituted
for Betapace AF because only Betapace AF is distributed with a patient package insert that is
appropriate for patients with AFIB/AFL.
Sotalol hydrochloride is contraindicated in patients with bronchial asthma, sinus bradycardia, second
and third degree AV block, unless a functioning pacemaker is present, congenital or acquired long QT
syndromes, cardiogenic shock, uncontrolled congestive heart failure, and previous evidence of
hypersensitivity to sotalol.
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. Sotalol hydrochloride 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, sotalol did not produce increased mortality at doses up to
320 mg/day (see Clinical Studies). 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.
Like other antiarrhythmic agents, sotalol 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 (QT
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 sotalol, 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
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 supraventricular 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 (QT
) interval, as
shown in the table below.
Percent Incidence of Torsade de Pointes and Mean QT
Interval by Dose For Patients With
Daily Dose (mg)
Incidence of Torsade de Pointes
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 QT
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 sotalol therapy was discontinued in
most patients experiencing Torsade de Pointes, 17% were continued on a lower dose.
Nonetheless, sotalol should be used with particular caution if the QT
is greater than 500 msec on-
therapy and serious consideration should be given to reducing the dose or discontinuing therapy when
highest on-therapy value
Number of patients assessed
exceeds 550 msec. Due to the multiple risk-factors associated with Torsade de Pointes,
however, caution should be exercised regardless of the QT
interval. The table below relates the
incidence of Torsade de Pointes to on-therapy QT
and change in QT
from baseline. It should be
noted, however, that the highest on-therapy QT
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 QT
Relationship Between QT
Interval Prolongation and Torsade de Pointes
( ) Number of patients assessed
Incidence of Torsade
Change in QT
Interval From Baseline
Incidence of Torsade
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 sotalol 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., PES or 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
sotalol in 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, sotalol hydrochloride tablets should be administered cautiously. Both digitalis and
sotalol slow 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 sotalol. 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 sotalol
(1.8% in 1395 Class I patients, 4.9% in 1254 Class II patients and 6.1% in 278 Class III or IV patients).
Sotalol 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.
Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be
avoided (see Proarrhythmia above). Sinus bradycardia (heart rate less than 50 bpm) occurred in 13%
of patients receiving sotalol 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
Recent Acute MI
Sotalol 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 sotalol 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
The following warnings are related to the beta-blocking activity of sotalol.
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 sotalol hydrochloride tablets, 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 sotalol hydrochloride tablets 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 sotalol hydrochloride tablets, 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 sotalol hydrochloride tablets are to be administered, to use the
smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous
catecholamine stimulation of beta 2 receptors may be minimized.
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.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major
surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment
the risks of general anesthesia and surgical procedures.
In patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous
hypoglycemia, sotalol hydrochloride tablets should be given with caution since beta-blockade may
mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.
Sick Sinus Syndrome
Sotalol hydrochloride tablets should be used only with extreme caution in patients with sick sinus
syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus
pauses or sinus arrest.
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.
Sotalol hydrochloride 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 sotalol.
Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND
Drugs undergoing CYP450 metabolism
Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are
not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any
CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these
Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III
drugs (e.g., amiodarone) are not recommended as concomitant therapy with sotalol, because of their
potential to prolong refractoriness (see WARNINGS). There is only limited experience with the
concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated
with the use of other beta-blocking agents concomitantly with sotalol.
Single and multiple doses of sotalol do not substantially affect serum digoxin levels. Proarrhythmic
events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this
represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in
the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular
conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Calcium blocking drugs
Sotalol should be administered with caution in conjunction with calcium-blocking drugs because of
possible additive effects on atrioventricular conduction or ventricular function. Additionally,
concomitant use of these drugs may have additive effects on blood pressure, possibly leading to
Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-
blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients treated with
sotalol plus a catecholamine depletor should therefore be closely monitored for evidence of
hypotension and/or marked bradycardia which may produce syncope.
Insulin and oral antidiabetics
Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment.
Symptoms of hypoglycemia may be masked.
Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased
dosages when used concomitantly with sotalol.
Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation
of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving sotalol.
No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.
Administration of sotalol within 2 hours of antacids containing aluminum oxide and magnesium
hydroxide should be avoided because it may result in a reduction in C
and AUC of 26% and 20%,
respectively and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the
antacid two hours after sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.
Drugs prolonging the QT interval
Sotalol should be administered with caution in conjunction with other drugs known to prolong the QT
interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants,
astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see WARNINGS).
Drug/Laboratory Test Interactions
The presence of sotalol in 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, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 275
mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5
times the MRHD as mg/m
) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day
(approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m
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 MRHD as mg/m
) 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/m
), respectively, did not reveal any teratogenic potential associated
with sotalol hydrochloride. In rabbits, a high dose of sotalol hydrochloride (160 mg/kg/day) at 16 times
the MRHD as mg/kg (6 times the MRHD as mg/m
) 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/m
not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol hydrochloride, 100
times the MRHD (18 times the MRHD as mg/m
), increased the number of early resorptions, while at
14 times the maximum dose (2.5 times the MRHD as mg/m
), 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, sotalol hydrochloride
has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of
subnormal birth weight with sotalol. Therefore, sotalol hydrochloride tablets should be used during
pregnancy only if the potential benefit outweighs the potential risk.
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 sotalol, 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.
The safety and effectiveness of sotalol in children have not been established. However, the Class III
electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the
effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children
aged between 3 days and 12 years old (see CLINICAL PHARMACOLOGY).
During premarketing trials, 3186 patients with cardiac arrhythmias (1363 with sustained ventricular
tachycardia) received oral sotalol, of whom 2451 received the drug for at least two weeks. The most
important adverse effects are Torsade de Pointes and other serious new ventricular arrhythmias (see
WARNINGS), occurring at rates of almost 4% and 1%, respectively, in the VT/VF population. Overall,
discontinuation because of unacceptable side-effects was necessary in 17% of all patients in clinical
trials, and in 13% of patients treated for at least two weeks. The most common adverse reactions leading
to discontinuation of sotalol are as follows: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea
3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%.
Occasional reports of elevated serum liver enzymes have occurred with sotalol therapy but no cause
and effect relationship has been established. One case of peripheral neuropathy which resolved on
discontinuation of sotalol and recurred when the patient was rechallenged with the drug was reported in
an early dose tolerance study. Elevated blood glucose levels and increased insulin requirements can
occur in diabetic patients.
The following table lists as a function of dosage the most common (incidence of 2% or greater)
adverse events, regardless of relationship to therapy and the percent of patients discontinued due to the
event as collected from clinical trials involving 1292 patients with sustained VT/VF
Incidence (%) of Adverse Events and Discontinuations
(n = 832)
(n = 263)
(n = 835)
(n = 459)
(n = 324)
(n = 1292)
Body as a whole
(n = 1292)
abnormal lab value
Mus culos keletal
Skin and Appendages
In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and
with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious
new arrhythmias were observed. One (1) patient, receiving 30 mg/m
daily, was discontinued because
of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90
and 210 mg/m
daily dose levels. They included QT prolongations (2 patients), sinus
pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient).
Values for QT
≥ 525 msec were seen in 2 patients at the 210 mg/m
daily dose level. Serious adverse
events including death, Torsade de Pointes, other proarrhythmias, high-degree A-V blocks and
bradycardia have been reported in infants and/or children.
Potential Adverse Effects
Foreign marketing experience with sotalol hydrochloride shows an adverse experience profile similar
to that described above from clinical trials. Voluntary reports since introduction include rare reports
(less than one report per 10,000 patients) of: emotional lability, slightly clouded sensorium,
incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity
reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, alopecia.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been associated
with sotalol during investigational use and foreign marketing experience.
Intentional or accidental overdosage with sotalol hydrochloride has rarely resulted in death.
Symptoms and Treatment of Overdosage
The most common signs to be expected are bradycardia, congestive heart failure, hypotension,
bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of sotalol
hydrochloride the following clinical findings were seen: hypotension, bradycardia, cardiac asystole,
prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular
complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed
closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma
concentrations. Patients should be carefully observed until QT intervals are normalized and the heart
Because patients are counted at each dose level tested, the Any Dose column cannot be determined by adding
across the doses.
rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be
associated with an initial slow drug elimination phase (half life of 30 hours) thought to be due to a
temporary reduction of renal function caused by the hypotension. In addition, if required, the following
therapeutic measures are suggested:
Bradycardia or Cardiac Asystole
Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.
(second and third degree) transvenous cardiac pacemaker.
(depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be
Aminophylline or aerosol beta-2-receptor stimulant.
Torsade de Pointes
DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.
DOSAGE AND ADMINISTRATION
As with other antiarrhythmic agents, sotalol hydrochloride tablets, USP should be initiated and doses
increased in a hospital with facilities for cardiac rhythm monitoring and assessment (see
INDICATIONS AND USAGE). Sotalol hydrochloride tablets, USP should be administered only after
appropriate clinical assessment (see INDICATIONS AND USAGE), and the dosage of sotalol
hydrochloride tablets, USP must be individualized for each patient on the basis of therapeutic response
and tolerance. Proarrhythmic events can occur not only at initiation of therapy, but also with each
upward dosage adjustment.
Dosage of sotalol hydrochloride tablets, USP should be adjusted gradually, allowing 3 days between
dosing increments in order to attain steady-state plasma concentrations, and to allow monitoring of QT
intervals. Graded dose adjustment will help prevent the usage of doses which are higher than necessary
to control the arrhythmia. The recommended initial dose is 80 mg twice daily. This dose may be
increased, if necessary, after appropriate evaluation to 240 or 320 mg/day (120 to 160 mg twice daily).
In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in
two or three divided doses. Some patients with life-threatening refractory ventricular arrhythmias may
require doses as high as 480 to 640 mg/day; however, these doses should only be prescribed when the
potential benefit outweighs the increased risk of adverse events, in particular proarrhythmia. Because
of the long terminal elimination half-life of sotalol, dosing on more than a BID regimen is usually not
As in adults the following precautionary measures should be considered when initiating sotalol
treatment in children: initiation of treatment in the hospital after appropriate clinical assessment;
individualized regimen as appropriate; gradual increase of doses if required; careful assessment of
therapeutic response and tolerability; and frequent monitoring of the QTc interval and heart rate.
For children aged about 2 years and greater
For children aged about 2 years and greater, with normal renal function, doses normalized for body
surface area are appropriate for both initial and incremental dosing. Since the Class III potency in
children (see CLINICAL PHARMACOLOGY) is not very different from that in adults, reaching
plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric
pharmacokinetic data the following is recommended.
For initiation of treatment, 30 mg/m
three times a day (90 mg/m
total daily dose) is approximately
equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m
(approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be
guided by clinical response, heart rate and QTc, with increased dosing being preferably carried out in-
hospital. At least 36 hours should be allowed between dose increments to attain steadystate plasma
concentrations of sotalol in patients with age-adjusted normal renal function.
For children aged about 2 years or younger
For children aged about 2 years or younger, the above pediatric dosage should be reduced by a factor
that depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in
For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years
or greater should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97)=29.1 mg/m
, administered three times daily. For a child aged 1 month, the starting dose should be multiplied by
0.68; the initial starting dose would be (30 X 0.68)=20 mg/m
, administered three times daily. For a
child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be
(30 X 0.3)=9 mg/m
. Similar calculations should be made for increased doses as titration proceeds.
Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state
will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer.
In all children, individualization of dosage is required. As in adults Betapace (sotalol hydrochloride)
should be used with particular caution in children if the QTc is greater than 500 msec on therapy, and
serious consideration should be given to reducing the dose or discontinuing therapy when QTc
exceeds 550 msec.
Dosage in Renal Impairment
Because sotalol is excreted predominantly in urine and its terminal elimination half-life is prolonged in
conditions of renal impairment, the dosing interval (time between divided doses) of sotalol should be
modified (when creatinine clearance is lower than 60 mL/min) according to the following table.
Dose should be individualized
Since the terminal elimination half-life of sotalol hydrochloride is increased in patients with renal
impairment, a longer duration of dosing is required to reach steady-state. Dose escalations in renal
impairment should be done after administration of at least 5 to 6 doses at appropriate intervals (see table
above). Extreme caution should be exercised in the use of sotalol in patients with renal failure
undergoing hemodialysis. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients.
Sotalol, however, can be partly removed by dialysis with subsequent partial rebound in concentrations
when dialysis is completed. Both safety (heart rate, QT interval) and efficacy (arrhythmia control) must
be closely monitored.
The use of sotalol hydrochloride in children with renal impairment has not been investigated. Sotalol
elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with
decreased renal function should be at lower doses or at increased intervals between doses. Monitoring
of heart rate and QT
is more important and it will take much longer to reach steady-state with any dose
and/or frequency of administration.
Transfer to Sotalol Hydrochloride Tablets, USP
Before starting sotalol hydrochloride tablets, USP, previous antiarrhythmic therapy should generally be
withdrawn under careful monitoring for a minimum of 2 to 3 plasma half-lives if the patient's clinical
condition permits (see Drug Interactions). Treatment has been initiated in some patients receiving I.V.
lidocaine without ill effect. After discontinuation of amiodarone, sotalol hydrochloride tablets, USP
should not be initiated until the QT interval is normalized (see WARNINGS).
Preparation of Extemporaneous Oral Solution
Information relating to the preparation of an extemporaneous oral solution of sotalol is approved for
Berlex Laboratories’ sotalol hydrochloride tablets. However, due to Berlex’s marketing exclusivity
rights, this drug product is not labeled with that information.
Transfer to Betapace AF from Sotalol Hydrochloride Tablets, USP
Patients with a history of symptomatic AFIB/AFL who are currently receiving sotalol hydrochloride
tablets, USP for the maintenance of normal sinus rhythm should be transferred to Betapace AF because
of the significant differences in labeling (i.e., patient package insert for Betapace AF, dosing
administration, and safety information).
Sotalol Hydrochloride Tablets, USP 80 mg are available for oral administration as white to off-white
capsule shaped, scored tablets, imprinted “APO” on one side and “SO” bisect “80” on the other side;
Overbagged with 10 tablets per bag, NDC 55154-8179-0
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
The initial dose of 80 mg and subsequent doses should be administered at these intervals. See following paragraph
for dosage escalations.
Controlled Room Temperature].
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
is a trademark of Berlex.
American Health Packaging
Columbus, OH 43217
Dublin, OH 43017
Package/Label Display Panel
Sotalol Hydrochloride Tablets, USP
sotalol hydrochloride tablet
Product T ype
HUMAN PRESCRIPTION DRUG
Ite m Code (Source )
NDC:55154-8 179 (NDC:6 8 0 8 4-6 54)
Route of Administration
Active Ingredient/Active Moiety
Basis of Strength
Stre ng th
SO TALO L HYDRO CHLO RIDE (UNII: HEC37C70 XX) (SOTALOL - UNII:A6 D9 7U29 4I)
8 0 mg
Stre ng th
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)
S hap e
OVAL (capsule shaped)
S iz e
Marketing Start Date
Marketing End Date
NDC:55154-8 179 -0
10 in 1 BAG
0 3/11/20 14
1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct
Marke ting Cate gory
Application Numbe r or Monograph Citation
Marke ting Start Date
Marke ting End Date
ANDA0 76 140
0 3/11/20 14
Cardinal Health (603638201)