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 Side Effects, and Drug Interactions - Sotalol Hydrochloride
Betapace Side Effects, and Drug Interactions - Sotalol Hydrochloride
SIDE EFFECTS
Adverse events that are clearly related to BETAPACE AFTM
are those which are typical of its Class II (beta-blocking) and Class III (cardiac
action potential duration prolongation) effects. The common documented beta-blocking
adverse events (bradycardia, dyspnea, and fatigue) and Class III effects (QT
interval prolongation) are dose related.
In a pooled clinical trial population consisting of four placebo-controlled
studies with 275 patients with AFIB/AFL treated with 160-320 mg doses of BETAPACE
AFTM , the following adverse events were reported at a rate of 2%
or more in the 160-240 mg treated patients and greater than the rate in placebo
patients (see Table 8). The data are presented by incidence of events in the
BETAPACE AFTM and placebo groups by body system and daily dose. No
significant irreversible non-cardiac end-organ toxicity was observed.
Table 8: Incidence (%) of Common Adverse Events (³2%
in the 160 –240 mg group and more frequent than on placebo) in Four Placebo-Controlled
Studies of Patients with AFIB/AFL
|
Body System/ Adverse Event (Preferred Term)
|
Placebo
|
Betapace AFTM Total Daily Dose
|
|
|
N=282
|
160 – 240 N=153
|
>240 – 320 N=122
|
|
CARDIOVASCULAR
|
|
|
|
|
Abnormality ECG
|
0.4
|
3.3
|
2.5
|
|
Angina Pectoris
|
1.1
|
2.0
|
1.6
|
|
Bradycardia
|
2.5
|
13.1
|
12.3
|
|
Chest pain Cardiac/Non-Anginal
|
4.6
|
4.6
|
2.5
|
|
Disturbance Rhythm Atrial
|
2.1
|
2.0
|
1.6
|
|
Disturbance Rhythm Subjective
|
9.9
|
9.8
|
7.4
|
|
GASTROINTESTINAL
|
|
|
|
|
Appetite Decreased
|
0.4
|
2.0
|
1.6
|
|
Diarrhea
|
2.1
|
5.2
|
5.7
|
|
Distention Abdomen
|
0.4
|
0.7
|
2.5
|
|
Dyspepsia/Heartburn
|
1.8
|
2.0
|
2.5
|
|
Nausea/Vomiting
|
5.3
|
7.8
|
5.7
|
|
Pain Abdomen
|
2.5
|
3.9
|
2.5
|
|
GENERAL
|
|
|
|
|
Fatigue
|
8.5
|
19.6
|
18.9
|
|
Fever
|
0.7
|
0.7
|
3.3
|
|
Hyperhidrosis
|
3.2
|
5.2
|
4.9
|
|
Influenza
|
0.4
|
2.0
|
0.8
|
|
Sensation Cold
|
0.7
|
2.0
|
2.5
|
|
Weakness
|
3.2
|
5.2
|
4.9
|
|
MUSCULOSKELETAL/CONNECTIVE TISSUE
|
|
|
|
|
Pain Chest Musculoskeletal
|
1.4
|
2.0
|
2.5
|
|
Pain Musculoskeletal
|
2.8
|
2.6
|
4.1
|
|
NERVOUS SYSTEM
|
|
|
|
|
Dizziness
|
12.4
|
16.3
|
13.1
|
|
Headache
|
5.3
|
3.3
|
11.5
|
|
Insomnia
|
1.1
|
2.6
|
4.1
|
|
RESPIRATORY
|
|
|
|
|
Cough
|
2.5
|
3.3
|
2.5
|
|
Dyspnea
|
7.4
|
9.2
|
9.8
|
|
Infection Upper Respiratory
|
1.1
|
2.6
|
3.3
|
|
Tracheobronchitis
|
0.7
|
0.7
|
3.3
|
|
SPECIAL SENSES
|
|
|
|
|
Disturbance Vision
|
0.7
|
2.6
|
0.8
|
Overall, discontinuation because of unacceptable adverse events
was necessary in 17% of the patients, and occurred in 10% of patients less than
two weeks after starting treatment. The most common adverse events leading to
discontinuation of BETAPACE AFTM were: fatigue 4.6%, bradycardia
2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.
In clinical trials involving 1292 patients with sustained VT/VF,
the common adverse
events (occurring in ³ 2%
of patients) were similar to those described for the AFIB/AFL population.
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.
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 also include rare reports of: emotional
lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia,
eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema,
hyperlipidemia, myalgia, pruritus, alopecia.
The oculomucocutaneous syndrome associated with the beta-blocker
practolol has not been associated with BETAPACE AFTM during investigational
use and foreign marketing experience.
DRUG INTERACTIONS
Drugs undergoing CYP450 metabolism: Pharmacokinetic
drug-drug interactions involving alteration of metabolism of sotalol are not
expected because hepatic CYP450 metabolizing enzymes are not involved in the
disposition of sotalol. Sotalol is primarily eliminated by renal excretion;
therefore, drugs that are metabolized by CYP450 are not expected to alter the
pharmacokinetics of sotalol.
Digoxin: 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.
Calcium blocking drugs: BETAPACE AFTM 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 hypotension.
Catecholamine-depleting agents: 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
BETAPACE AFTM 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-2-receptor stimulants: Beta-agonists such as salbutamol,
terbutaline and isoprenaline may have to be administered in increased dosages
when used concomitantly with BETAPACE AFTM.
Clonidine: Beta-blocking drugs may potentiate the rebound
hypertension sometimes observed after discontinuation of clonidine; therefore,
caution is advised when discontinuing clonidine in patients receiving BETAPACE
AFTM.
Other: No pharmacokinetic interactions were observed
with hydrochlorothiazide or warfarin.
Antacids: Administration of BETAPACE AFTM
within 2 hours of antacids containing aluminum oxide and magnesium hydroxide
should be avoided because it 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 BETAPACE AFTM
has no effect on the pharmacokinetics or pharmacodynamics of sotalol.
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, 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 MRHD as 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 sotalol HCl. In rabbits, a high dose of sotalol HCl
(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
sotalol HCl, 100 times the MRHD (18 times the MRHD as 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, sotalol HCl 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, BETAPACE AFTM 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 AFTM,
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
AFTM in children have not been established.
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