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 Pharmacology, Pharmacokinetics, Studies, Metabolism - Sotalol Hydrochloride
Betapace Pharmacology, Pharmacokinetics, Studies, Metabolism - Sotalol Hydrochloride
CLINICAL PHARMACOLOGY
Mechanism of Action: BETAPACE AFTM (sotalol
hydrochloride) has both beta-adrenoreceptor blocking (Vaughan Williams Class
II) and cardiac action potential duration prolongation (Vaughan Williams Class
III) antiarrhythmic properties. BETAPACE AFTM (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.
Electrophysiology: 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, slows 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 BETAPACE AFTM 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 40-100 msec in QT and 10-40 msec in QTc. In a study of patients
with atrial fibrillation (AFIB)/flutter (AFIB/AFL) receiving three different
oral doses of BETAPACE AFTM given q12h (or q24h in patients with
a reduced creatinine clearance), mean increases in QT intervals measured from
12-lead ECGs of 25 msec, 40 msec and 54 msec were found in the 80 mg, 120 mg
and 160 mg dose groups, respectively. (See WARNINGS
for description of relationship between QTc 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 2-15 joules) compared to a mean of 16 joules for a non-randomized
comparative group primarily receiving amiodarone.
In a dose-response trial comparing three dose levels of BETAPACE
AFTM, 80 mg, 120 mg, and 160 mg with placebo given q12h (or q24h
in patients with a reduced renal creatinine clearance) for the prevention of
recurrence of symptomatic atrial fibrillation (AFIB)/flutter (AFL), the mean
ventricular rate during recurrence of AFIB/AFL was 125, 107, 110 and 99 beats/min
in the placebo, 80 mg, 120 mg and 160 mg dose groups, respectively (p<0.017
for each sotalol dose group versus placebo). In another placebo controlled trial
in which BETAPACE AFTM was titrated to a dose between 160 and 320
mg/day in patients with chronic AFIB, the mean ventricular rate during recurrence
of AFIB was 107 and 84 beats/min in the placebo and BETAPACE AFTM
groups, respectively (p<0.001) .
Hemodynamics: 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 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 non-significant 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 produces significant reductions
in both systolic and diastolic blood pressures. Although sotalol 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.).
Clinical Studies:
Prolongation of Time to Recurrence of Symptomatic Atrial Fibrillation/Flutter
BETAPACE AFTM 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 AFTM (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 not randomized 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 hypomagnesiemia
(serum magnesium < 1.5 meq/L); received chronic oral amiodarone therapy for
> 1 month within previous12 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 ³
520 msec (or JT ³ 430 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 AFTM 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 1 and Tables 1 and 2.
|
Table 1: Study 1 – Patient Status At 12 Months
|
|
|
Placebo
|
Betapace AF Dose
|
|
80 mg
|
120 mg
|
160mg
|
|
Randomized
|
69
|
59
|
63
|
62
|
|
On treatment in NSR at 12 months without recurrencea
|
23%
|
22%
|
29%
|
23%
|
|
Recurrencea, b
|
67%
|
58%
|
49%
|
42%
|
|
D/C for AEs
|
6%
|
12%
|
18%
|
29%
|
a Symptomatic AFIB/AFL
b Efficacy endpoint of Study 1; study treatment
stopped
Please note that columns do not add up to 100% due to discontinuations
(D/C) for "other" reasons.
Table 2: Study 1 – Median Time to Recurrence of Symptomatic
AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months
|
|
Placebo
|
Betapace AF Dose
|
|
80 mg
|
120 mg
|
160 mg
|
|
p-value vs placebo
|
|
p=0.325
|
p=0.018
|
p=0.029
|
|
Relative Risk (RR) to placebo
|
|
0.81
|
0.59
|
0.59
|
|
Median time to Recurrence (days)
|
27
|
106
|
229
|
175
|
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 AFTM
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 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 AFTM (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%).
Figure 2 and Tables 3 and 4 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 3: Study 2 - Patient Status At 6 Months
|
|
|
Betapace AF
|
Placebo
|
|
Randomized
|
118
|
114
|
|
On treatment in NSR at 6 months without recurrencea
|
45%
|
29%
|
|
Recurrencea, b
|
49%
|
67%
|
|
D/C for AEs
|
6%
|
3%
|
|
Death
|
|
1%
|
a Symptomatic or asymptomatic AFIB/AFL
b Efficacy endpoint of Study 2; study treatment
stopped
Table 4: Study 2 – Median Time to Recurrence of Symptomatic
AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months
| |
Betapace AF
|
Placebo
|
|
p-value vs placebo
|
p=0.002
|
|
|
Relative Risk (RR) to placebo
|
0.55
|
|
|
Median time to recurrence(days)
|
>180
|
44
|
Safety in Patients with Structural Heart Disease:
In a multicenter double-blind randomized study reported by
D. Julian et al, the effect of sotalol 320 mg once daily was compared with that
of placebo in 1456 patients (randomized 3:2, sotalol to placebo) surviving an
acute myocardial infarction (MI). Treatment was started 5-14 days after infarction.
Patients were followed for 12 months. The mortality rate was 7.3% in the sotalol
group and 8.9% in the placebo group, not a statistically significant difference.
Although the results do not show evidence of a benefit of sotalol in this population,
they do not show an added risk in post MI patients receiving sotalol.
Pharmacokinetics: 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 (i.e., 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. 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 does not bind to plasma proteins and is not metabolized.
Sotalol shows very little intersubject variability in plasma levels. The pharmacokinetics
of the d and l enantiomers of sotalol are essentially identical. Sotalol 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 , but impaired
renal function in geriatric patients can increase the terminal elimination half-life,
resulting in increased drug accumulation. The absorption of sotalol was reduced
by approximately 20% compared to fasting when it was administered with a standard
meal. Since sotalol is not subject to first-pass metabolism, patients with hepatic
impairment show no alteration in clearance of sotalol.
top
