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
Betapace Pharmacology, Pharmacokinetics, Studies, Metabolism - Sotalol
CLINICAL PHARMACOLOGY
Mechanism of Action
BETAPACE® (sotalolhydrochloride) has both beta-adrenoreceptor
blocking (Vaughan Williams
Class II) and cardiac action potential
duration prolongation
(Vaughan Williams Class III) antiarrhythmic properties. BETAPACE®
(sotalolhydrochloride) 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 sotalolis 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, 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, 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 BETAPACE® 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. (see WARNINGS for description
of relation ship 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 BETAPACE®, 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.
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 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 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 BETAPACE®, and total peripheral
resistance increases
by a small amount.
In hypertensive
patients, BETAPACE® (sotalolhydrochloride) produces significant
reductions in both systolic
and diastolic blood
pressures. Although BETAPACE® (sotalolhydrochloride) 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 Actions
BETAPACE® (sotalol hydrochloride) has been studied in life-threatening
and less severe arrhythmias. In patients with frequent premature
ventricular complexes
(VPC), BETAPACE® (sotalolhydrochloride) 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® (sotalolhydrochloride) 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® (sotalolhydrochloride)
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® (sotalolhydrochloride)
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 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 p.o. 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® (sotalolhydrochloride)
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
(e.g., in patients with implanted defibrillators) whether BETAPACE®
response causes improved
survival or identifies a population
with a good prognosis.
In a large double-blind, placebo
controlled secondary
prevention (post-infarction)
trial (n=1,456), BETAPACE® (sotalolhydrochloride) 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 sotalolvs.
2% on placebo). In a second
small trial (n=17 randomized to sotalol) where sotalolwas 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.
Pharmacokinetics
In healthy
subjects, the oral bioavailability
of BETAPACE® (sotalolhydrochloride) 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 BETAPACE®
(sotalolhydrochloride) 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.
BETAPACE® (sotalolhydrochloride) does not bind
to plasma proteins and
is not metabolized. BETAPACE® (sotalolhydrochloride) shows very
little intersubject variability
in plasma levels. The
pharmacokinetics of the d and l enantiomers of sotalolare essentially
identical. BETAPACE® (sotalolhydrochloride) 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 BETAPACE®,
but impaired renal function
in geriatric patients can increase the terminal
elimination half-life,
resulting in increased drug
accumulation. The absorption
of BETAPACE® (sotalolhydrochloride) was reduced by approximately
20% compared to fasting
when it was administered with a standard
meal. Since BETAPACE® (sotalolhydrochloride) is not subject
to first-pass metabolism,
patients with hepatic
impairment show no
alteration in clearance
of BETAPACE®.
top
