Mechanism Of Action
Sotalol has both
beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action
potential duration prolongation (Vaughan Williams Class III) antiarrhythmic
properties. The two isomers of sotalol 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/m² body surface area (BSA). A reduction of the
resting heart rate due to the beta-blocking effect of sotalol is observed at
daily doses ≥ 90 mg/m² in children.
Cardiac Electrophysiological Effects
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 atrioventricular
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 40–100 msec in QT and 10–40 msec in QTc [See WARNINGS AND PRECAUTIONS]. No significant alteration
in QRS interval is observed.
In a small study (n=25) of patients with implanted
defibrillators treated concurrently with Betapace, the average defibrillatory
threshold was 6 joules (range 2–15 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 SVT and/or ventricular 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/m² with dosing every 8 hours for a total 9
doses. During steady-state, the respective average increases above baseline of
the QTc interval were 2, 14, and 29 msec at the 3 dose levels. The respective
mean maximum increases above baseline of the QTc interval were 23, 36, and 55
msec at the 3 dose levels. The steady-state percent increases in the RR
interval were 3, 9 and 12%. The smallest children (BSA < 0.33 m²) showed a
tendency for larger Class III effects (ΔQTc) and an increased frequency of
prolongations of the QTc interval as compared with larger children (BSA
≥ 0.33 m²). The beta-blocking effects also tended to be greater in the
smaller children (BSA < 0.33 m²). Both the Class III and beta-blocking
effects of sotalol were linearly related to the plasma concentrations.
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 Betapace 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. One patient was discontinued because of worsening
congestive heart failure. Pulmonary capillary wedge pressure increased
significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the
study. Mean arterial pressure, mean pulmonary artery pressure and stroke work
index did not significantly change. Exercise and isoproterenol induced
tachycardia are antagonized by Betapace, and total peripheral resistance
increases by a small amount.
In hypertensive patients, sotalol produces significant
reductions in both systolic and diastolic blood pressures. Although sotalol is
usually well-tolerated hemodynamically, deterioration in cardiac performance
may occur in patients with marginal cardiac compensation [see WARNINGS AND PRECAUTIONS].
The pharmacokinetics of the d and l enantiomers of
sotalol are essentially identical.
In healthy subjects, the oral bioavailability of sotalol
is 90–100%. After oral administration, peak plasma concentrations are reached
in 2.5 to 4 hours, and steady-state plasma concentrations are attained within
2–3 days (that is, after 5–6 doses when administered twice daily). Over the
dosage range 160–640 mg/day sotalol displays dose proportionality with respect
to plasma concentrations. When administered with a standard meal, the
absorption of sotalol was reduced by approximately 20% compared to
administration in fasting state.
Sotalol does not bind to plasma proteins. Distribution
occurs to a central (plasma) and to a peripheral compartment. Sotalol crosses
the blood brain barrier poorly.
Sotalol is not metabolized and is not expected to inhibit
or induce any CYP450 enzymes.
Excretion of sotalol is predominantly via the kidney in
the unchanged form, and therefore lower doses are necessary in conditions of
renal impairment [see DOSAGE AND ADMINISTRATION]. The mean elimination
half-life of sotalol is 12 hours. Dosing every 12 hours results in trough
plasma concentrations which are approximately one-half of those at peak.
Pediatric: The combined analysis of a single-dose study
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/m² of sotalol was administered in the single dose study and daily doses of
30, 90 and 210 mg/m² were administered every 8 hours in the multi-dose study.
After rapid absorption with peak levels occurring on average between 2–3 hours
following administration, sotalol was eliminated with a mean half-life of 9.5
hours. Steady-state was reached after 1–2 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 < 0.33m²) 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%.
Geriatric: Age does not significantly alter the
pharmacokinetics of Betapace/Betapace AF, but impaired renal function in
geriatric patients can increase the terminal elimination half-life, resulting
in increased drug accumulation.
Renal Impairment: Sotalol 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. The half-life of sotalol is prolonged (up to 69 hours) in anuric
patients. Doses or dosing intervals should be adjusted based on creatinine
clearance [see DOSAGE AND ADMINISTRATION].
Hepatic Impairment: Patients with hepatic
impairment show no alteration in clearance of sotalol.
Antacids: Administration of oral sotalol within 2
hours of antacids may result in a reduction in Cmax 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 oral sotalol has no effect
on the pharmacokinetics or pharmacodynamics of sotalol.
No pharmacokinetic interactions were observed with
hydrochlorothiazide or warfarin.
Betapace (sotalol hydrochloride) has been studied in
life-threatening and less severe arrhythmias. In patients with frequent
premature ventricular complexes (VPC), Betapace (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 80–85% of patients having at least a 75% reduction of
VPCs. Betapace was also superior, at the doses evaluated, to propranolol (40–80
mg TID) and similar to quinidine (200–400 mg QID) in reducing VPCs. In patients
with life-threatening arrhythmias [sustained ventricular
tachycardia/fibrillation (VT/VF)], Betapace 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 Betapace and
procainamide given intravenously (total of 2 mg/kg Betapace vs. 19 mg/kg of
procainamide over 90 minutes), Betapace 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 Betapace was compared with that of 6 other drugs (procainamide,
quinidine, mexiletine, propafenone, imipramine and pirmenol). Overall response,
limited to first randomized drug, was 39% for Betapace and 30% for the pooled
other drugs. Acute response rate for first drug randomized using suppression of
PES induction was 36% for Betapace 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), Betapace 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), Betapace, 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
75–80%). The most commonly used doses of Betapace in this trial were 320– 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 Betapace vs. no pharmacologic treatment (for example,
in patients with implanted defibrillators) whether Betapace response causes
improved survival or identifies a population with a good prognosis.
Betapace has not been shown to enhance survival in
patients with ventricular arrhythmias.
Clinical Studies In Supra-ventricular Arrhythmias
Betapace AF has been studied in patients with symptomatic
AFIB/AFL in two principal studies, one in patients with primarily paroxysmal
AFIB/AFL, the other in patients with primarily chronic AFIB.
In one study, a U.S. multicenter, randomized,
placebo-controlled, double-blind, dose-response trial of patients with
symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of Betapace
AF (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253
patients. In patients with reduced creatinine clearance (40-60 mL/min) the same
doses were given once daily. Patients were excluded for the following reasons:
QT > 450 msec; creatinine clearance < 40 mL/min; intolerance to
beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted
pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic
CVA or TIA; acute myocardial infarction within the previous 2 months;
congestive heart failure; bronchial asthma or other contraindications to
beta-blocker therapy; receiving potassium losing diuretics without potassium
replacement or without concurrent use of ACE-inhibitors; uncorrected
hypokalemia (serum potassium < 3.5 meq/L) or hypomagnesemia (serum magnesium
< 1.5 meq/L); received chronic oral amiodarone therapy for > 1 month within
previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade
de Pointes with other antiarrhythmic agents which increase the duration of
ventricular repolarization; sinus rate < 50 bpm during waking hours; unstable
angina pectoris; receiving treatment with other drugs that prolong the QT
interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW)
syndrome. If the QT interval increased to ≥ 520 msec (or JT ≥ 430
msec if QRS > 100 msec) the drug was discontinued. The patient population in
this trial was 64% male, and the mean age was 62 years. No structural heart
disease was present in 43% of the patients. Doses were administered once daily
in 20% of the patients because of reduced creatinine clearance.
Betapace AF was shown to prolong the time to the first
symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the
risk of such recurrence at both 6 and 12 months. The 120 mg dose was more
effective than 80 mg, but 160 mg did not appear to have an added benefit. Note
that these doses were given twice or once daily, depending on renal function.
The results are shown in Figure 2, Table 7 and Table 8.
Figure 2: Study 1 – Time to First ECG-Documented
Recurrence of Symptomatic AFIB/AFL Since Randomization
Table 7: Study 1 – Patient
Status at 12 Months
||Betapace AF Dose
|On treatment in NSR at 12 months without recurrencea
|D/C for AEs
|a Symptomatic AFIB/AFL
b Efficacy endpoint of Study 1; study treatment stopped.
Note that columns do not add up to 100% due to
discontinuations (D/C) for “other” reasons.
Table 8: Study 1 – Median
Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at
|Betapace AF Dose
|P-value vs. placebo
|Relative Risk (RR) to placebo
|Median time to recurrence (days)
Discontinuation because of
adverse events was dose related.
In a second multicenter,
randomized, placebo-controlled, double-blind study of 6 months duration in 232
patients with chronic AFIB, Betapace AF was titrated over a dose range from 80
mg/day to 320 mg/day. The patient population of this trial was 70% male with a
mean age of 65 years. Structural heart disease was present in 49% of the
patients. All patients had chronic AFIB for > 2 weeks but < 1 year at entry
with a mean duration of 4.1 months. Patients were excluded if they had
significant electrolyte imbalance, QTc > 460 msec, QRS > 140 msec, any
degree of AV block or functioning pacemaker, uncompensated cardiac failure,
asthma, significant renal disease (estimated creatinine clearance < 50
mL/min), heart rate < 50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective
endocarditis, active pericarditis or myocarditis, ≥ 3 DC cardioversions
in the past, medications that prolonged QT interval, and previous amiodarone
treatment. After successful cardioversion patients were randomized to receive
placebo (n=114) or Betapace AF (n=118), at a starting dose of 80 mg twice
daily. If the initial dose was not tolerated it was decreased to 80 mg once
daily, but if it was tolerated it was increased to 160 mg twice daily. During
the maintenance period 67% of treated patients received a dose of 160 mg twice
daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg
twice daily (16%).
Tables 9 and 10 show the
results of the trial. There was a longer time to ECG-documented recurrence of
AFIB and a reduced risk of recurrence at 6 months compared to placebo.
Table 9: Study 2 – Patient
Status at 6 Months
|On treatment in NSR at 6 months without recurrencea
|D/C for AEs
|a Symptomatic or asymptomatic AFIB/AFL
b Efficacy endpoint of Study 2; study treatment stopped.
Table 10: Study 2 – Median Time to Recurrence of
Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months
|P-value vs. placebo
|Relative Risk (RR) to placebo
|Median time to recurrence (days)
|| > 180
Figure 3: Study 2 – Time to
First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since
Clinical Studies In Patients With
In a large double-blind,
placebo controlled secondary prevention (postinfarction) trial (n=1,456);
Betapace (sotalol hydrochloride) was given as a non-titrated initial dose of
320 mg once daily. Betapace did not produce a significant increase in survival
(7.3% mortality on Betapace 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 Betapace vs. 2% on placebo).
In a second small trial (n=17
randomized to Betapace) where Betapace was administered at high doses (for
example, 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 Betapace.