Proarrhythmia

Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization (QTc interval prolongation), torsade de pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis is the most common form of proarrhythmia associated with sotalol, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of torsade de pointes progressively increases with prolongation of the QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (see Electrolyte Disturbances).

Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and the patient's underlying rhythm disorder. (Note, however, that torsade de pointes is usually a drug-induced arrhythmia in people with an initially normal QTc.) Thus, the incidence of drug-related events cannot be precisely determined, so that the occurrence rates provided must be considered approximations. Note also that drug-induced arrhythmias may often not be identified, particularly if they occur long after starting the drug, due to less frequent monitoring. It is clear from the NIH-sponsored CAST (seeWARNINGS: Mortality) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole, that do not appear early in treatment but that represent a sustained increased risk.

Overall in clinical trials with sotalol, 4.3% of 3257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular tachycardia in approximately 1% of patients and torsade de pointes in 2.4%. Additionally, in approximately 1% of patients, deaths were considered possibly drug-related; such cases, although difficult to evaluate, may have been associated with proarrhythmic events.In patients with a history of sustained ventricular tachycardia, the incidence of torsade de pointes was 4% and worsened VT in about 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of torsade de pointes was 1% and 1.4%, respectively.

Torsade de pointes arrhythmias were dose related, as is the prolongation of QT (QTc) interval, as shown in the table below.

Percent Incidence of Torsade de Pointes and Mean QTC Interval by Dose For Patients with Sustained VT/VF

Daily Dose (mg)	Incidence of Torsade de Pointes	Mean QTca (msec)
80	0 (69)b	463 (17)
160	0.5 (832)	467 (181)
320	1.6 (835)	473 (344)
480	4.4 (459)	483 (234)
640	3.7 (324)	490 (185)
640	5.8 (103)	512 (62)

aHighest on-therapy value
bNumber of patients assessed

In addition to dose and presence of sustained VT, other risk factors for torsade de pointes were gender (females had a higher incidence), excessive prolongation of the QTc interval (see table below) and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appear to have the highest risk for serious proarrhythmia (7%). Of the patients experiencing torsade de pointes, approximately two-thirds spontaneously reverted to their baseline rhythm. The others were either converted electrically (D/C cardioversion or overdrive pacing) or treated with other drugs (seeOVERDOSAGE). It is not possible to determine whether some sudden deaths represented episodes of torsade de pointes, but in some instances sudden death did follow a documented episode of torsade de pointes. Although sotalol therapy was discontinued in most patients experiencing torsade de pointes, 17% were continued on a lower dose.

Nonetheless, sotalol should be used with particular caution if the QTc is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc exceeds 550 msec. Due to the multiple risk factors associated with torsade de pointes, however, caution should be exercised regardless of the QTc interval. The table below relates the incidence of torsade de pointes to on-therapy QTc and change in QTc from baseline. It should be noted, however, that the highest on-therapy QTc was in many cases the one obtained at the time of the torsade de pointes event, so that the table overstates the predictive value of a high QTc.

Relationship Between QTc Interval Prolongation and Torsade de Pointes

On-Therapy QTc Interval (msec)	Incidence of Torsade de Pointes	Change in QTc Interval From Baseline (msec)	Incidence of Torsade de Pointes
<500	1.3% (1787)	<65	1.6% (1516)
500 to 525	3.4% (236)	65 to 80	3.2% (158)
525 to 550	5.6% (125)	80 to 100	4.1% (146)
550	10.8% (157)	100 to 130	5.2% (115)
		130	7.1% (99)

( ) Number of patients assessed

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (torsade de pointes and worsened VT) occurred within 7 days of initiating sotalol therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg BID with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of sotalol in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION).

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 Dose****a (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.

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 include rare reports (less than one report per 10,000 patients) of: emotional lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, alopecia.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been associated with sotalol during investigational use and foreign marketing experience.

PRECAUTIONS

Renal Impairment

Sotalol hydrochloride 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. Guidance for dosing in conditions of renal impairment can be found underDOSAGE AND ADMINISTRATION.

Drug Interactions

Drugs undergoing CYP450 metabolism

Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes.

Antiarrhythmics

Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with sotalol, because of their potential to prolong refractoriness (seeWARNINGS). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with sotalol.

Digoxin

Single and multiple doses of sotalol do not substantially affect serum digoxin levels. 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. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Calcium-blocking drugs

Sotalol 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 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 (seeWARNINGS).

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 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, sotalol hydrochloride 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 children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (seeCLINICAL PHARMACOLOGY).