Sotalol Hydrochloride (Page 4 of 6)

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 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-2-receptor stimulants

Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol.

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 sotalol.

Other

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Antacids

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 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 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/m2) 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/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 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/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 hydrochloride, 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 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.

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 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.

Pediatric Use

The safety and effectiveness of sotalol in pediatric patients have not been established. However, information relating to the clinical pharmacology in pediatric patients is approved for Berlex Laboratories’ sotalol hydrochloride tablets. Due to Berlex’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

ADVERSE REACTIONS

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
DAILY DOSE
Body System

160 mg

(n = 832)

240 mg

(n = 263)

320 mg

(n = 835)

480 mg

(n = 459)

640 mg

(n = 324)

Any Dosea

(n = 1292)

% Patients Discontinued (n = 1292)

Body as a whole
infection 1 2 2 2 3 4 < 1
fever 1 2 3 2 2 4 < 1
localized pain 1 1 2 2 2 3 < 1
Cardiovascular
dyspnea 5 8 11 15 15 21 2
bradycardia 8 8 9 7 5 16 2
chest pain 4 3 10 10 14 16 < 1
palpitation 3 3 8 9 12 14 < 1
edema 2 2 5 3 5 8 1
ECG abnormal 4 2 4 2 2 7 1
hypotension 3 4 3 2 3 6 2
proarrhythmia < 1 < 1 2 4 5 5 3
syncope 1 1 3 2 5 5 1
heart failure 2 3 2 2 2 5 1
presyncope 1 2 2 4 3 4 < 1
peripheral vascular disorder 1 2 1 1 2 3 < 1
cardiovascular disorder 1 < 1 2 2 2 3 < 1
vasodilation 1 < 1 1 2 1 3 < 1
AICD discharge < 1 2 2 2 2 3 < 1
hypertension < 1 1 1 1 2 2 < 1
Nervous
fatigue 5 8 12 12 13 20 2
dizziness 7 6 11 11 14 20 1
asthenia 4 5 7 8 10 13 1
light-headed 4 3 6 6 9 12 1
headache 3 2 4 4 4 8 < 1
sleep problem 1 1 5 5 6 8 < 1
perspiration 1 2 3 4 5 6 < 1
altered consciousness 2 3 1 2 3 4 < 1
depression 1 2 2 2 3 4 < 1
paresthesia 1 1 2 3 2 4 < 1
anxiety 2 2 2 3 2 4 < 1
mood change < 1 < 1 1 3 2 3 < 1
appetite disorder 1 2 2 1 3 3 < 1
stroke < 1 < 1 1 1 < 1 1 < 1
Digestive
nausea/vomiting 5 4 4 6 6 10 1
diarrhea 2 3 3 3 5 7 < 1
dyspepsia 2 3 3 3 3 6 < 1
abdominal pain < 1 < 1 2 2 2 3 < 1
colon problem 2 1 1 < 1 2 3 < 1
flatulence 1 < 1 1 1 2 2 < 1
Respiratory
pulmonary problem 3 3 5 3 4 8 < 1
upper respiratory tract problem 1 1 3 4 3 5 < 1
asthma 1 < 1 1 1 1 2 < 1
Urogenital
genitourinary disorder 1 0 1 1 2 3 < 1
sexual dysfunction < 1 1 1 1 3 2 < 1
Metabolic
abnormal lab value 1 2 3 2 1 4 < 1
weight change 1 1 1 < 1 2 2 < 1
Musculoskeletal
extremity pain 2 2 4 5 3 7 < 1
back pain 1 < 1 2 2 2 3 < 1
Skin and Appendages
rash 2 3 2 3 4 5 < 1
Hematologic
bleeding 1 < 1 1 < 1 2 2 < 1
Special Senses
visual problem 1 1 2 4 5 5 < 1

a) Because patients are counted at each dose level tested, the Any Dose column cannot be determined by adding across the doses.

In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m2 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/m2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m2 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 QTC ≥ 525 msec were seen in 2 patients at the 210 mg/m2 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.

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