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APOTEX CORP
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60505008100

sotalol 160 mg tablet

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Uses

Sotalol is used to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia) and to maintain normal sinus rhythm in patients with symptomatic atrial fibrillation or flutter who are currently in sinus rhythm. Some experts state that sotalol may be used for the treatment of monomorphic ventricular tachycardia or preexcited atrial arrhythmias (associated with an accessory pathway).

The choice of a β-adrenergic blocking agent depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.

Ventricular Arrhythmias

Sotalol is used to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia) and is designated an orphan drug by the FDA for such use.

It remains to be established whether antiarrhythmic agents, including sotalol, have a beneficial effect on mortality or sudden death. Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s Cardiac Arrhythmia Suppression Trial (CAST) after an average of 10 months of follow-up have indicated that the rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild to moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent ventricular premature complexes [VPC]) who received encainide or flecainide (class I antiarrhythmic drugs) increased substantially compared with placebo. Therefore, the FDA and some experts recommend that use of class I antiarrhythmic drugs in patients with ventricular arrhythmias be limited to those with life-threatening arrhythmias. It has been suggested that the applicability of these results from class I antiarrhythmic agents to predominantly class III antiarrhythmic agents, such as sotalol, a drug that is devoid of class I effects, is uncertain. Like other antiarrhythmic agents, sotalol can worsen existing arrhythmias or cause new arrhythmias, including torsades de pointes. Because of the drug's arrhythmogenic potential, use of sotalol for less severe arrhythmias, even if symptomatic, is not recommended by the manufacturer, and treatment of asymptomatic VPCs should be avoided.

The manufacturers recommend that sotalol therapy and subsequent dosage increases be initiated in an institutional setting. In addition, before progressing to chronic therapy, suitable (e.g., programmed electrical stimulation [PES], Holter) monitoring should be employed to evaluate potential antiarrhythmic efficacy.

Life-threatening Ventricular Arrhythmias and Advanced Cardiovascular Life Support

Antiarrhythmic drugs are used during cardiac arrest to facilitate and maintain a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest. High-quality cardiopulmonary resuscitation (CPR) and defibrillation are integral components of advanced cardiovascular life support (ACLS) and the only proven interventions to increase survival to hospital discharge. Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation. The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is considered the drug of choice for this use. Antiarrhythmic drugs may be considered for the treatment of refractory ventricular fibrillation or pulseless ventricular tachycardia during cardiac resuscitation; however, experts generally recommend the use of amiodarone (or lidocaine). IV sotalol may be used for the management of regular wide-complex tachycardias during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for adult tachycardia.

Although comparative data are limited, oral or IV sotalol generally is considered to be as effective as some other antiarrhythmic agents (e.g., procainamide, quinidine) for the management of severe refractory arrhythmias. Data from clinical studies indicate that the drug is effective in approximately 55-85% of patients with life-threatening ventricular arrhythmias, including those refractory to other antiarrhythmic agents. Sotalol can reduce VPCs, paired VPCs, and nonsustained ventricular tachycardia in patients with frequent VPCs and can suppress the recurrence of ventricular tachyarrhythmias in patients with ventricular tachycardia and/or fibrillation. The drug also has suppressed Holter monitor evidence of sustained ventricular tachycardia and ventricular tachycardia induced by PES. Although sotalol has been reported to reduce the risk of death from any cause and from cardiac causes compared with several class I antiarrhythmics (e.g., mexiletine, procainamide, propafenone, quinidine) in patients with ventricular tachyarrhythmias, the drug has not been shown to have a benefit in terms of long-term survival or neurologic outcome.

Sotalol may be used for the treatment of hemodynamically stable patients with monomorphic ventricular tachycardia. Although rare, episodes of sustained polymorphic ventricular tachycardia (electrical storm) that are associated with acute myocardial infarction and are refractory to initial antiarrhythmic drug therapy (e.g., lidocaine, procainamide) should be managed by aggressive attempts at reducing myocardial ischemia, including therapies such as an IV β-adrenergic blocking agent, intra-aortic balloon counterpulsation, and/or emergency revascularization (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft [CABG] surgery); IV amiodarone also may be useful.

Supraventricular Arrhythmias

Sotalol appears to be effective in the suppression and prevention of various supraventricular tachycardias (SVTs), including atrial fibrillation or flutter and paroxysmal supraventricular tachycardia (PSVT). Because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents such as sotalol generally should be reserved for patients who do not respond to or cannot be treated with AV nodal blocking agents (β-adrenergic blocking agents and nondihydropyridine calcium-channel blocking agents).

Atrial Fibrillation and Flutter

Oral sotalol is used in maintaining normal sinus rhythm in patients with symptomatic atrial fibrillation or flutter who are currently in sinus rhythm. Some experts state that sotalol may be used in patients with preexcited atrial arrhythmias. However, synchronized cardioversion is the intervention of choice. Because selected class III antiarrhythmic agents have the potential to cause life-threatening ventricular arrhythmias, the manufacturer states that sotalol should be reserved for the treatment of highly symptomatic atrial fibrillation.(See Cautions: Arrhythmogenic Effects.) In addition, patients with paroxysmal atrial fibrillation that is easily reversed (e.g., by the Valsalva maneuver) should not receive sotalol. If atrial fibrillation has been present for more than 48 hours, a risk of systemic embolization exists with conversion to sinus rhythm unless the patient is adequately anticoagulated.

Available data suggest that the efficacy of oral sotalol for prevention of recurrences of atrial fibrillation or flutter is comparable to that of quinidine or propafenone and less than that of amiodarone. Maintenance of sinus rhythm with oral sotalol does not appear to be related to either duration of previous episodes of atrial fibrillation (e.g., paroxysmal or persistent atrial fibrillation) or the degree of atrial enlargement.

Other Supraventricular Tachycardias

Sotalol also has been used in patients with other SVTs, including paroxysmal supraventricular tachycardia (PSVT) due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT). However, many experts prefer vagal maneuvers and IV adenosine as initial therapeutic choices for the treatment of PSVT in patients without contraindications to these therapies. Sotalol may be a reasonable choice of therapy for the ongoing management of patients with symptomatic SVT who are not candidates for, or prefer not to undergo, catheter ablation and in whom first-line drugs (e.g., β-adrenergic blocking agents, diltiazem, verapamil) are not effective or are contraindicated.

Dosage and Administration

Administration

Sotalol hydrochloride is administered orally. While food reportedly can reduce the oral bioavailability of sotalol hydrochloride by about 20%, the manufacturer states that the drug may be administered with or without food. To ensure maximum efficacy, sotalol hydrochloride should be administered at approximately the same time(s) each day. Administration of sotalol hydrochloride tablets orally within 2 hours of administration of an aluminum oxide and magnesium hydroxide-containing antacid resulted in decreased absorption of sotalol as evidenced by 26 and 20% reductions in peak plasma sotalol concentrations and concentration-time curve (AUC), respectively. Since such decreased absorption was associated with a 25% reduction in bradycardic effect, the manufacturer states that antacids should not be administered within 2 hours of administration of sotalol; however, when the antacid was administered 2 hours after sotalol, no effects on the pharmacokinetics or pharmacodynamics of sotalol were observed.

Dosage

Dosage of sotalol hydrochloride must be adjusted carefully according to individual requirements and response, patient tolerance, renal function, and general condition and cardiovascular status of the patient. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during therapy with the drug. Because of the arrhythmogenic potential of the drug and the life-threatening nature of the arrhythmias against which the drug is being employed, the manufacturer recommends that patients be monitored for at least 3 days on their maintenance dosage following initiation, reinitiation, and, if necessary, dosage titration in a setting (e.g., institutional setting) that can provide cardiac resuscitation, continuous ECG monitoring, and calculations of creatinine clearance. Patients being treated for supraventricular arrhythmias (atrial fibrillation or flutter) should not be discharged from such a setting within 12 hours of pharmacologic or electrical cardioversion to normal sinus rhythm. Proarrhythmic effects of sotalol must be anticipated, and therapy with the drug should be initiated only by personnel skilled in the management of serious ventricular arrhythmias (e.g., sustained ventricular tachycardia such as torsades de pointes).Arrhythmogenic events occur most often during the initial 7 days of instituting sotalol therapy or an upward dosage adjustment. About 75% of such serious events (e.g., torsades de pointes, worsened ventricular tachycardia) occur within 7 days of initiating therapy with the drug, whereas 60% occur within 3 days of initiation of the drug or dosage adjustment. Avoiding excess accumulation of the drug in patients with diminished renal function by appropriate dosage adjustment also should reduce this risk.

Modification of sotalol hydrochloride dosage based on age alone is not necessary; however, appropriate adjustments should be made for those with impaired renal function.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment) Patients should be advised not to double the next dose if a dose is missed; instead, they should wait until the next scheduled dose, resuming the prescribed regimen at that time.

Life-Threatening Ventricular Arrhythmias

For the suppression and prevention of life-threatening ventricular tachyarrhythmias in adults, the usual initial dosage of sotalol hydrochloride is 80 mg twice daily. Initiating therapy at a sotalol hydrochloride dosage of 80 mg twice daily with gradual upward titration and appropriate monitoring for efficacy (e.g., PES, Holter) and safety (e.g., QT interval, heart rate, electrolytes) prior to dose escalation should reduce the risk of precipitating arrhythmias. If necessary, dosage may be increased gradually after appropriate evaluation to 240-320 mg daily given in divided doses, allowing 3 days between dosing increments to allow for attainment of steady-state plasma concentrations of sotalol.

The usual adult maintenance dosage is 160-320 mg daily given in divided doses. Although sotalol hydrochloride can be given in 2 or 3 divided doses daily, dosing more frequently than twice daily usually is not necessary since the drug has a long terminal elimination half-life. In patients with life-threatening refractory ventricular arrhythmias, dosage may be increased to 480-640 mg daily given in divided doses; however, because the risk of potentially serious toxicity increases with dose, such relatively high dosages should be employed only when the potential benefits outweigh the possible risks, particularly arrhythmogenic risks.

Supraventricular Arrhythmias

Initiation and Dosage Titration

Dosage of sotalol hydrochloride in patients with a history of atrial fibrillation or flutter must be adjusted carefully and individualized according to renal function and to the QT interval. For the acute management of persistent atrial fibrillation or flutter in adults with normal renal function (a creatinine clearance exceeding 60 mL/minute) and a near normal QT interval (450 msec or less), an 80 mg twice-daily dosage of sotalol hydrochloride should be given initially. If a dose is missed, the patient should take only the next scheduled dose (i.e., the next dose should not be doubled); doubling the dosage may increase the risk of sotalol-induced arrhythmias. Patients receiving sotalol should be advised of the importance of taking the drug exactly as prescribed, and of contacting their clinician if a higher than prescribed dosage is taken. Alternatively, in patients with a baseline QRS interval exceeding 100 msec, the JT interval may be used to adjust dosage; sotalol is contraindicated in patients with a baseline JT interval of 330 msec or greater. Therapy in patients with baseline prolongation of the QT interval (exceeding 450 msec) is not recommended, as new arrhythmias (e.g., torsades de pointes) may develop. The QTc interval should be determined 2-4 hours after each dose of sotalol during the inpatient dosage titration phase. In patients with normal renal function during the inpatient dosage-titration phase, sotalol should be discontinued or dosage of the drug reduced if the QT interval is 500 msec or greater. Prolongation of the QT interval is dose-related, increasing from baseline an average of 25, 40, and 50 msec for doses of 80, 120, and 160 mg, respectively, twice daily in a dose-ranging study. If patients are well controlled (e.g., no recurrences of atrial fibrillation or flutter) during the first 3 days of inpatient monitoring at 80 mg twice daily and the QT interval remains less than 500 msec, the patient may be discharged on current treatment but should be given an adequate supply of sotalol hydrochloride to allow uninterrupted therapy until they have their outpatient prescription filled.

If recurrences of atrial fibrillation or flutter occur during initiation of therapy, the dosage may be increased gradually after appropriate evaluation to 120 or 160 mg twice daily (the maximum recommended dosage), allowing 3 days (or 5 or 6 doses if once-daily dosing is used) of inpatient monitoring between dosing increments. Patients who experience a recurrence of atrial fibrillation or flutter after completing the inpatient monitoring phase despite therapy at a dosage lower than the maximum recommended dosage of 160 mg twice daily should be readmitted to a facility that can provide cardiac resuscitation, continuous ECG monitoring, and calculation of creatinine clearance for an additional 3 days (or 5 or 6 doses if once-daily dosing is used) of monitoring for each increase in dosage up to a maximal dosage of 160 mg twice daily. Therapy with dosages exceeding 160 mg twice daily is not recommended for the management of atrial fibrillation or flutter, as these dosages have been associated with an increased incidence of torsades de pointes. In a large dose-ranging study, the 120-mg twice-daily dosage was the most effective dosage in delaying the time to a recurrence of atrial fibrillation or flutter.

Adjunctive Antithrombotic Therapy

One of the goals of treatment of persistent atrial fibrillation is prevention of thromboembolism. Adequate anticoagulation is necessary for resolution of pre-existing atrial thrombi and for the prevention of new thrombi that may occur following cardioversion, particularly in those whose arrhythmia is of greater than 48 hours' duration. Patients with persistent atrial fibrillation, especially geriatric patients younger than 75 years of age, and those with hypertension, atrial and ventricular dysfunction, diabetes mellitus, recent heart failure, or prior history of stroke or transient ischemic attacks must be adequately anticoagulated (as measured by an International Normalized Ratio [INR] of 2-3), generally for at least 3 weeks before administration of antiarrhythmic agents and continued for 4 weeks after cardioversion. In marginal patients, in addition to anticoagulation, consultation with a cardiologist and diagnostic procedures to exclude atrial thrombi are indicated to assess the risks and benefits of therapeutic strategies. In patients who require earlier cardioversion, transesophageal echocardiography may be used to identify atrial thrombi, and patients without preexisting thrombi may receive anticoagulation with heparin, cardioversion within 1-2 days of initiation of anticoagulation, followed by administration of warfarin for 4 weeks. Patients who cannot tolerate anticoagulation may be given aspirin to prevent stroke.

Maintenance Dosage

Upon discharge, measurement of creatinine clearance and the QT interval should be performed periodically as medically warranted. If the QT interval is 520 msec or longer or if the JT interval is 430 msec or longer in patients with a QRS interval exceeding 100 msec, the dosage of sotalol hydrochloride should be reduced and the patient monitored until the QT or JT interval returns to less than 520 or 430 msec, respectively. If the QT interval is 520 msec or longer at the lowest maintenance dosage of 80 mg twice daily, the drug should be discontinued.

Patients being Transferred from other Antiarrhythmic Agents

The manufacturer recommends a transition period for patients being transferred from another antiarrhythmic agent to sotalol hydrochloride. In general, the current antiarrhythmic agent should be withdrawn and initiation of sotalol therapy delayed for at least 2-3 elimination half-lives of the other drug; the patient should be monitored carefully during this period. However, in patients being transferred from amiodarone, sotalol therapy should be withheld until the QT interval has normalized. Sotalol therapy has been initiated in some patients prior to discontinuance of IV lidocaine therapy without ill effect.

Patients with a history of symptomatic atrial fibrillation or flutter who are receiving Betapace for maintenance of sinus rhythm should be transferred to Betapace AF because of appreciable differences in labeling.

Dosage in Renal and Hepatic Impairment

Dosage of sotalol hydrochloride should be adjusted according to the degree of renal impairment in patients with creatinine clearances less than 60 mL/minute.

The manufacturer states that clearance of sotalol is not altered by impaired hepatic function.

Life-threatening Ventricular Arrhythmias

In patients being treated for ventricular arrhythmias, sotalol hydrochloride therapy can be initiated with the usual initial adult dose of 80 mg; however, the frequency of administration should be modified according to the following table:

Creatinine Clearance (mL/min) Dosing Interval (hours)
30-59 24
10-29 36-48
<10 individualize

Since the terminal elimination half-life of the drug is increased in patients with renal impairment, each incremental increase in sotalol hydrochloride dosage should be made only after a given dose has been repeated at least 5 or 6 times at the dosing interval appropriate for the degree of renal impairment. Sotalol should be administered with extreme caution in patients with renal failure undergoing hemodialysis since elimination half-life in anuric patients may be prolonged (up to 69 hours). However, since the drug is partially removed by dialysis, plasma sotalol concentrations usually rebound when dialysis is completed. These patients should be monitored closely for efficacy in arrhythmia control and adverse effects (changes in heart rate and/or QT interval).

Supraventricular Arrhythmias

Patients beginning therapy should be observed in a setting that can provide dosage adjustments based on creatinine clearance and continuous ECG monitoring (e.g., QT interval) for at least 5-6 days (when steady-state plasma concentrations are reached) after initiation of sotalol administration. The patient's creatinine clearance (Ccr) can be estimated by using the following formula:

Ccr male = [(140 - age) x weight (in kg)] / [72 x serum creatinine (in mg/dL)]Ccr female = 0.85 x Ccr male

If serum creatinine concentrations is given in mcmol/L, the value should be divided by 88.4 (1 mg/dL = 88.4 mcmol/L).

An initial oral sotalol hydrochloride dosage of 80 mg once daily is recommended for patients with creatinine clearances of 40-60 mL/minute being treated for supraventricular arrhythmias (atrial fibrillation or flutter). If a dose is missed, the patient should take only the next scheduled dose (i.e., the next dose should not be doubled); doubling the dosage may increase the risk of sotalol-induced arrhythmias. Use of sotalol for the management of supraventricular arrhythmias in patients with a creatinine clearance of less than 40 mL/minute is contraindicated. Therapy in patients with baseline prolongation of the QT interval (exceeding 450 msec) also is contraindicated, as new arrhythmias (e.g., torsades de pointes) may develop. Alternately, if the QRS interval exceeds 100 msec, therapy with sotalol should not be initiated if the JT interval is 330 msec or greater. The QTc interval should be determined 2-4 hours after each dose of sotalol. If the QTc interval is prolonged to 500 msec or greater after the first or subsequent daily dosage, dosage of the drug should be reduced or the drug discontinued. If the arrhythmia is well controlled (e.g., no recurrences of atrial fibrillation or flutter) during inpatient monitoring of the first 5-6 doses at 80 mg once daily and the QT interval remains below 500 msec, the patient may be discharged on current treatment. If recurrences of atrial fibrillation or flutter occur during initiation of therapy at a daily dosage of 80 mg, dosage may be increased gradually after appropriate evaluation to 120 or 160 mg once daily, allowing inpatient monitoring for 5-6 doses between dosing increments. Achievement of steady-state plasma concentrations is delayed in patients with renal impairment compared with adults with normal renal function, and each incremental increase in sotalol hydrochloride dosage should be made only after steady state has been reached (5 or 6 days).

For recurrences of atrial fibrillation or flutter after completion of the inpatient monitoring phase despite therapy at a dosage lower than the maximum recommended dosage of 160 mg once daily in patients with renal impairment, the patient should be readmitted to a facility that can provide cardiac resuscitation, continuous ECG monitoring, and calculation of creatinine clearance for monitoring of an additional 5-6 doses for each increase in the daily dosage of 40 mg, up to a maximum dosage of 160 mg once daily. Therapy with dosages exceeding 160 mg once daily in patients with renal impairment is not recommended, as these dosages have been associated with an increased incidence of torsades de pointes. In a large study evaluating fixed dosages of sotalol hydrochloride (80, 120, or 160 mg twice daily) in patients being treated for atrial fibrillation or flutter, adjustment of the dosage interval to once daily for renal impairment was required in about 20% of all patients.

Cautions

Sotalol shares the toxic potentials of nonselective β-adrenergic blocking agents and, in therapeutic dosage, generally is well tolerated during long-term therapy. However, as a class III antiarrhythmic agent (see Description), sotalol, unlike conventional β-blockers, can precipitate torsades de pointes. In clinical trials, the adverse effect profile for common adverse effects was similar for patients receiving sotalol for supraventricular arrhythmias (i.e., atrial fibrillation or flutter) versus for ventricular arrhythmias (i.e., sustained ventricular tachycardia or fibrillation).

The most serious adverse effects of sotalol are torsades de pointes and other new ventricular arrhythmias, which occurred in almost 4, 1, or 0.6%, respectively, of patients with underlying sustained ventricular tachycardia, ventricular fibrillation, or atrial fibrillation or flutter in clinical trials. The most frequent adverse effects of sotalol involve the cardiovascular and nervous systems and GI tract, and occasionally they may be severe enough to require discontinuance of the drug. The most common adverse effects resulting in discontinuance of the drug include effects usually associated with β-blockade. Fatigue caused discontinuance of sotalol in 4-5% of patients, bradycardia (heart rate less than 50 bpm) in 2-3%, dyspnea in 2-3%, arrhythmogenic effects in 2-3%, asthenia in 2%,dizziness in 2% and QT interval prolongation in 1.4% of patients receiving the drug in clinical trials. Overall, discontinuance of sotalol as a result of adverse effects occurred in 17% of patients receiving the drug in clinical trials and in 10-13% of those treated for at least 2 weeks. Generally, sotalol may be better tolerated than and the incidence of adverse effects severe enough to require discontinuance of the drug may be lower than with many other (e.g., class I) antiarrhythmic agents (e.g., mexiletine, procainamide, propafenone, quinidine). Abrupt withdrawal of sotalol should be avoided, especially in patients with coronary artery disease, since it may exacerbate angina or precipitate myocardial infarction.

Arrhythmogenic Effects

Like other antiarrhythmic agents, sotalol can worsen existing arrhythmias or cause new arrhythmias, including sustained ventricular tachycardia or ventricular fibrillation which potentially may be fatal, and the arrhythmogenic potential is the most serious risk associated with the drug. Because sotalol prolongs the QT interval corrected for rate (QTc), torsades de pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis, is the most common arrhythmogenic effect of the drug, occurring in about 0.6 or 4% of patients with a history of supraventricular arrhythmias (i.e., atrial fibrillation or flutter) or ventricular arrhythmias (i.e., sustained ventricular tachycardia or ventricular fibrillation), respectively. The risk of torsades de pointes increases progressively with prolongation of the QT interval and is worsened by a reduction in heart rate and serum potassium concentration.(See Cautions: Precautions and Contraindications.)

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; however, torsades de pointes usually is a drug-induced arrhythmia in patients with an initial normal QTc interval. Since the frequency of drug-related events cannot be determined precisely, reported occurrence rates must be considered approximations. In addition, drug-induced arrhythmias often may go undetected, especially if they occur long after therapy with the drug is started because of less frequent monitoring; some antiarrhythmic drugs can cause increased sudden death mortality, apparently as a result of new arrhythmias or asystole, that does not appear early in treatment but that represents a sustained increased risk.

New or worsened ventricular arrhythmia occurred in 4.3% of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials and required discontinuance of the drug in 3% of patients. New or worsened sustained ventricular tachycardia occurred in about 1% of patients and torsades de pointes in about 2.4% of patients with a history of ventricular arrhythmias. In patients with a history of sustained ventricular tachycardia, torsades de pointes occurred in 4% and worsened ventricular tachycardia in about 1%; in patients with other, less serious ventricular arrhythmias or supraventricular arrhythmias, the frequency of torsades de pointes was 1 or 1.4%, respectively. ECG abnormalities occurred in 2.5-3.3% of patients with a history of atrial fibrillation or flutter receiving sotalol in controlled clinical trials. Pooled data from numerous clinical trials in a limited number of patients with atrial fibrillation or flutter indicate that atrial arrhythmias occurred in 2% of patients receiving sotalol. Subjective descriptions of rhythm disturbances were noted in 7.4-9.8% of patients with a history of atrial fibrillation or flutter receiving sotalol in controlled clinical trials. Such deaths were not reported in clinical trials involving use of sotalol for supraventricular arrhythmias (i.e., atrial fibrillation or flutter), but the manufacturer warns that experience in patients treated for ventricular arrhythmias is pertinent in assessing risk (e.g., of torsades de pointes) in those treated for supraventricular arrhythmias.

In clinical trials of sotalol, the incidence of cardiac mortality was 3.8% overall and 5.9% in patients with sustained ventricular tachycardia or ventricular fibrillation. In addition, in about 1% of patients, deaths were considered possibly drug related; although such cases may be difficult to evaluate, they may have been associated with arrhythmogenic events. Overall, cardiac death was associated with low left ventricular ejection fraction, history of congestive heart failure and/or cardiomegaly, and increasing age; the risk of death in patients with a history of both cardiomegaly and congestive heart failure was more than 3 times that in patients with no history of either condition. In patients with sustained ventricular tachycardia or ventricular fibrillation, the risk of cardiac death was most strongly associated with a history of cardiomegaly and then with a history of congestive heart failure and low left ventricular ejection fraction. A clear relationship between sotalol dosage and the frequency of death has not been demonstrated to date.

Prolongation of the QTc interval and the occurrence of torsades de pointes are related to sotalol dosage. In patients with sustained ventricular tachycardia or ventricular fibrillation, the frequency of torsades de pointes ranged from 0.5% at 160 mg daily to 1.6% at 320 mg daily but increased more abruptly at higher dosages, to about 4% at 480-640 mg daily and to almost 6% at higher dosages. In clinical trials of patients with a history of atrial fibrillation or flutter, the frequency of torsades de pointes was 0.3% in those receiving recommended dosages of sotalol of less than 240-320 mg daily; the frequency of torsades de pointes rose to 3.2% at higher dosages, with both cases in clinical trials of these atrial arrhythmias occurring at a dosage of 640 mg daily. Similarly, the frequency of torsades de pointes in patients with a history of ventricular arrhythmias was 1.6% when the change in QTc interval was less than 65 msec but increased by about 1% with each additional increase of about 20-30 msec in the QTc interval, with a frequency of 7.1% at QTc interval increases exceeding 130 msec. In addition, the risk of sotalol-induced torsades de pointes was increased with female gender, reduced renal function, large doses of the drug, and a history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appeared to be at greatest risk of a serious arrhythmogenic event, with an occurrence rate of 7%. Approximately two-thirds of patients experiencing sotalol-induced torsades de pointes reverted spontaneously to their baseline rhythm. The remaining patients required either cardioversion or overdrive pacing or treatment with other drugs. Although it is not possible to determine whether some sudden deaths resulted from episodes of torsades de pointes, some instances of sudden death did follow documented episodes. Most cases of torsades de pointes required discontinuance of sotalol therapy, but 17% of patients continued the drug at a lower dosage. Sotalol should be used with particular caution if the QTcinterval exceeds 500 msec during treatment, and dosage reduction or discontinuance of the drug should be considered seriously when the QTc interval exceeds 550 msec. Regardless of the QTc interval, caution should be exercised because of the multiple risk factors associated with torsades de pointes.

Sotalol-induced arrhythmogenic events occur most often during the initial 7 days of instituting therapy or an upward dosage adjustment. About 75% of such serious events (e.g., torsades de pointes, worsened ventricular tachycardia) occur within 7 days of initiating therapy with the drug, and about 60% occur within 3 days of initiation of the drug or dosage adjustment. Initiation of sotalol therapy at low dosages with gradual upward titration and appropriate monitoring should reduce the risk of arrhythmogenic events. Because of the arrhythmogenic potential of the drug and the life-threatening nature of the arrhythmias against which the drug is being employed, the manufacturer recommends that both initiation of sotalol therapy and any subsequent upward dosage adjustments be performed in an institutional setting.

Cardiovascular Effects

Sympathetic stimulation is necessary for supporting circulatory function in congestive heart failure. Therefore, because of its β-adrenergic blocking effects, sotalol may cause or worsen congestive heart failure, particularly in patients with preexisting heart failure (New York Heart Association [NYHA] class II-IV) or sustained ventricular tachycardia or ventricular fibrillation, and/or a history of cardiomegaly, cardiomyopathy, coronary artery disease, or myocardial infarction. The effect of these risk factors appears to be cumulative, with patients exhibiting more risk factors being at greater risk for precipitated or worsened congestive heart failure during therapy with the drug.

New or worsened congestive heart failure occurred in 3.3% of patients receiving sotalol in premarketing studies and required discontinuance of the drug in about 1% of patients. The frequency of new or worsened congestive heart failure was 4.6% in patients with sustained ventricular tachycardia or ventricular fibrillation and 7.3% in patients with a history of heart failure. In patients with sustained ventricular tachycardia or ventricular fibrillation, the most reliable predictive risk factors were a history of congestive heart failure or cardiomegaly. The 1-year frequency of new or worsened congestive heart failure was 3% in patients without a previous history and 10% in those with a previous history of congestive heart failure. The risk of new or worsened heart failure was closely related to NYHA classification. The occurrence of congestive heart failure was not related to dosage of sotalol, regardless of congestive heart failure history. New or worsened congestive heart failure occurred in 2.7% of patients with nonsustained ventricular tachycardia or VPCs and in 2.3% of patients with supraventricular arrhythmias. Pooled data from several clinical trials in patients with a history of atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia without moderately severe to severe congestive heart failure (i.e., New York Heart Association functional classes III or IV) indicate that new or exacerbated congestive heart failure occurred in 1.2% of these patients receiving sotalol.

Chest pain and palpitation, which appear to be dose related, occurred in 16 and 14%, respectively, of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials, but each of these adverse effects required discontinuance of the drug in less than 1% of patients. In pooled data from several clinical trials in a limited number of patients with atrial fibrillation or flutter, angina pectoris occurred in 3.3% of patients receiving sotalol 160-240 mg daily. Nonanginal chest pain occurred in 2.5-4.6% of patients with a history of atrial fibrillation or flutter receiving sotalol in controlled clinical trials. Edema was reported in 8%, abnormal ECG in 7%, and syncope in 5% of patients with a history of ventricular arrhythmias receiving sotalol, and each of these adverse effects required discontinuance of the drug in 1% of patients. Hypotension was reported in 6% of patients with a history of ventricular arrhythmias and required discontinuance in 2% of patients. Presyncope was reported in 4%; peripheral vascular disorder, cardiovascular disorder, vasodilation, or AICD discharge in 3%; and hypertension in 2% of patients with a history of ventricular arrhythmias receiving sotalol, and each of these adverse effects required discontinuance of the drug in less than 1% of patients.

Effects on Cardiac Conduction

Sinus bradycardia (heart rate less than 50 bpm), which increases the risk of torsades de pointes, occurred in 13% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and required discontinuance of the drug in about 3% of patients. Pooled data from several clinical trials in a limited number of patients with supraventricular arrhythmias indicate that bradycardia occurred in 12-13% of patients receiving sotalol; discontinuance of therapy was required in 2.4% of these patients. Sinus pause, arrest, and nodal dysfunction occurred in less than 1% of patients with a history of ventricular arrhythmias. Second- or third-degree AV block occurs in about 1% of patients receiving sotalol with a history of ventricular arrhythmias.

PR and QRS intervals are affected minimally by sotalol; however, at dosages of 160-640 mg daily, sotalol causes dose-related mean increases of 40-100 msec in the QT interval and 10-40 msec in the QTc interval. Excessive prolongation of the QT interval (to greater than 550 msec) can promote serious arrhythmias and should be avoided during sotalol therapy.(See Cautions: Arrhythmogenic Effects.)

Nervous System Effects

Fatigue and dizziness, which appear to be dose related, are the most common adverse nervous system effects of sotalol, occurring in 20% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving the drug in clinical trials. Fatigue and dizziness also are the most common adverse nervous system effects of sotalol in patients with a history of supraventricular arrhythmias (i.e., atrial fibrillation or flutter), occurring in 18.9-19.6 or 13.1-16.3% of these patients, respectively. Fatigue resulted in discontinuance of sotalol in 4 or 4.6% of patients with a history of supraventricular arrhythmias, respectively, and dizziness resulted in discontinuance of the drug in 2% of patients. Lightheadedness, dizziness, and syncope also are symptoms of torsades de pointes. Asthenia and lightheadedness, which also appear to be dose related, were reported in 13 and 12%, respectively, of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials and required discontinuance of the drug in 2 and 1% of patients, respectively. Weakness was reported in about 5% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials. Headache and sleep disturbances were reported in 8% of patients with a history of ventricular arrhythmias receiving sotalol and required discontinuance in less than 1% of patients. Insomnia was reported in 2.6-4.1% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials. Perspiration was reported in 6% of patients; altered consciousness, depression, paresthesia, or anxiety in 4% of patients; and localized pain, mood change, or appetite disorder in 3% of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials; each of these adverse effects required discontinuance of the drug in less than 1% of patients. Cold sensation was reported in 2-2.5% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials. Rarely, emotional lability, slightly clouded sensorium, incoordination, vertigo, and paralysis have been reported. One case of peripheral neuropathy, which resolved on discontinuance of sotalol therapy and recurred when the patient was rechallenged with the drug, also has been reported in patients with a history of ventricular arrhythmias.

Respiratory Effects

Dyspnea is the most frequently reported adverse effect of sotalol in patients with ventricular arrhythmias, occurring in 21% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving the drug in clinical trials but requiring discontinuance of therapy in only 3% of patients. Dyspnea has also been reported in 9.2-9.8% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials, requiring discontinuance of therapy in 2% of these patients. Pulmonary problems were reported in 8%, upper respiratory tract problems in 5%, and asthma in 2% of patients with a history of ventricular arrhythmias receiving sotalol; each of these adverse effects required discontinuance of therapy in less than 1% of patients. Influenza or upper respiratory tract infection has been reported in 0.8-2 or 2.6-3.3% of patients with a history of supraventricular arrhythmias (i.e., atrial fibrillation or flutter) receiving sotalol, respectively, in clinical trials. Cough or tracheobronchitis has been reported in 2.5-3.3 or 0.7-3.3% of patients with a history of these supraventricular arrhythmias receiving sotalol in clinical trials. Rarely, pulmonary edema has been reported in patients with a history of ventricular arrhythmias. As with other nonselective β-adrenergic blocking agents, sotalol can increase airway resistance by inhibiting bronchodilation mediated by endogenous or exogenous catecholamine stimulation of β2-adrenergic receptors; such changes may be clinically important in patients with underlying airway disease.(See Cautions: Precautions and Contraindications.)

GI Effects

Nausea and vomiting are the most frequent adverse GI effects of sotalol, occurring in 5.7-7.8 or 10% of patients with supraventricular (i.e., atrial fibrillation or flutter) or ventricular (i.e., sustained ventricular tachycardia or ventricular fibrillation) arrhythmias receiving the drug in clinical trials and requiring discontinuance in up to 1% of patients. Other adverse GI effects each required discontinuance of sotalol in less than 1% of patients with a history of ventricular arrhythmias. Diarrhea and dyspepsia were reported in 7 and 6%, respectively, of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials. Diarrhea or dyspepsia was reported in 5.2-5.7 or 2-2.5% of patients, respectively, with a history of supraventricular arrhythmias receiving sotalol in controlled clinical trials. Abdominal pain and colon problems occurred in 3% of patients, and flatulence occurred in 2% of patients with a history of ventricular arrhythmias. Abdominal pain or abdominal distension was reported in 2.5-3.9 % or 0.7-2.5% of patients with a history of supraventricular arrhythmias receiving sotalol, respectively, in controlled clinical trials.

Hepatic Effects

Increased serum concentrations of hepatic enzymes have occurred occasionally with sotalol therapy, but a causal relationship to the drug has not been established.

Genitourinary Effects

Genitourinary disorders and sexual dysfunction were reported in 3 and 2%, respectively, of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and each required discontinuance of the drug in less than 1% of patients.

Musculoskeletal Effects

Extremity pain and back pain were reported in 7 and 3%, respectively, of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and each required discontinuance of the drug in less than 1% of patients. Rarely, myalgia has been reported in patients with history of ventricular arrhythmias. Musculoskeletal pain or musculoskeletal chest pain has been reported in patients with a history of supraventricular arrhythmias (i.e., atrial fibrillation or flutter) in 2.6-4.1 or 2-2.5% of patients receiving sotalol in clinical trials, respectively.

Dermatologic Effects

Rash was reported in 5% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients. Rarely, photosensitivity reactions, pruritus, and alopecia have been reported in patients with a history of ventricular arrhythmias. Hyperhidrosis has been reported in 5% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.

Hematologic Effects

Bleeding was reported in 2% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients. Rarely, thrombocytopenia, leukopenia, and eosinophilia have been reported in patients with a history of ventricular arrhythmias.

Ocular Effects

Visual disorders were reported in 5% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients. Visual disturbances were reported in 0.8-2.6% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials. The oculomucocutaneous syndrome associated with the β-blocker practolol has not been associated with sotalol to date.

Other Adverse Effects

Fever, infection, and abnormal laboratory test results were each reported in 4% of patients and weight change in 2% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving sotalol in clinical trials, and each of these adverse effects required discontinuance of the drug in less than 1% of patients. Pooled data from several clinical trials in patients with a history of atrial fibrillation or flutter indicate that fever was reported in 0.7-3.3% of patients receiving sotalol. Increases in blood glucose concentration and insulin requirements can occur in patients with diabetes mellitus receiving sotalol. Rarely, hyperlipidemia has been reported in patients with a history of ventricular arrhythmias.

Precautions and Contraindications

Clinicians and patients should be aware that sotalol is marketed in the US under separate trade names for ventricular or atrial arrhythmias (Betapace or Betapace AF, respectively) and that the professional and patient labeling differ (e.g., for cautions, precautions, and contraindications; patient instructions and advice; and dosage and administration) for the respective commercially available products. Therefore, it is important that the information specific to the respective indication be followed and that patients be given the patient instructions provided by the manufacturer that are specific to the prescribed use.

Sotalol shares the toxic potentials of other nonselective β-adrenergic blocking agents, and the usual precautions of these agents should be observed. In addition, as a class III antiarrhythmic agent, sotalol, unlike conventional β-blockers, can precipitate torsades de pointes.

Sotalol, like other antiarrhythmics, has been associated with the development or exacerbation of arrhythmias in some patients.(See Cautions: Arrhythmogenic Effects.) Concerns about the long-term safety and efficacy of several antiarrhythmic agents (e.g., encainide, flecainide, moricizine) in patients with nonlife-threatening arrhythmias have been raised by findings of the postmarketing Cardiac Arrhythmia Suppression Trial (CAST).Findings from the CAST study after an average of 10 months of follow-up indicate that the rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild-to-moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent VPCs) who received encainide or flecainide was increased substantially. (For additional information on the CAST study, .) Similar life-threatening adverse consequences have been reported with moricizine. The relevance of these findings to other patient populations (e.g., those without recent myocardial infarction, those with life-threatening ventricular arrhythmias) and to other class I antiarrhythmic agents currently is not known.

While sotalol hydrochloride can be used safely and effectively in the chronic management of life-threatening ventricular arrhythmias following myocardial infarction, experience with the drug in the management of arrhythmias during the early phase of recovering from an acute myocardial infarction is limited and at least at high initial doses (i.e., nontitrated initial dosage of 320 mg daily or 320 mg twice daily) has not been reassuring. Sotalol is devoid of class I antiarrhythmic activity, and there was no evidence of excess mortality associated with sotalol hydrochloride dosages up to 320 mg daily in a large (1456 patients), controlled trial in patients with recent myocardial infarction (but not necessarily concurrent ventricular arrhythmias). However, in patients who received an initial (i.e., not titrated) dosage of 320 mg daily in this study and in high-risk postinfarction patients who received high dosages (320 mg twice daily) in a smaller study, there was some evidence of a possible excess in early (within 2 weeks) sudden deaths. Therefore, sotalol should be used cautiously and careful titration of dosage emphasized if the drug is used during the first 2 weeks following an acute myocardial infarction, particularly in patients with markedly impaired ventricular function. Although specific studies of sotalol in treating supraventricular arrhythmias after a recent myocardial infarction have not been performed to date, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia, or prolonged QT interval apply.

Since sotalol, like other antiarrhythmic agents, can worsen existing arrhythmias or cause new arrhythmias in some patients, clinical and ECG evaluations are essential prior to and during sotalol therapy to monitor for the appearance of arrhythmias and to determine the need for continued therapy or dosage adjustment. Arrhythmogenic events must be anticipated not only when sotalol therapy is initiated, but also with each upward dosage titration. To minimize the risk of arrhythmogenic effects, the recommendations for initiation of sotalol therapy and dosage adjustments should be closely followed.(See Dosage and Administration: Dosage.) In addition, excessive accumulation of the drug in patients with diminished renal function should be avoided by appropriate dosage adjustment. Because of the arrhythmogenic potential of the drug and the life-threatening nature of the arrhythmias against which the drug is being employed, the manufacturer recommends that initiation, reinitiation, and, if necessary, dosage titration of sotalol therapy be monitored for a minimum of 3 days (on the maintenance dosage) in a setting (e.g., institutional setting) that can provide cardiac resuscitation, continuous ECG monitoring, and calculations of renal function.

Sotalol increases QTc interval in a dose-related fashion and thereby increases the risk of torsades de pointes. Therefore, the QT interval should be monitored 2-4 hours after each dose for at least 3 days after initiation, reinitiation, and, if necessary, dosage titration of sotalol therapy, and dosage adjusted accordingly. Sotalol should not be initiated in patients with a QT interval exceeding 450 msec in patients with a history of atrial fibrillation or flutter. The drug should be used with particular caution when the QTc interval exceeds 500 msec during treatment. Excessive prolongation of the QT interval (to greater than 550 msec) can promote serious arrhythmias and should be avoided during sotalol therapy. Serious consideration should be given to reducing sotalol dosage or discontinuing the drug when the QTc interval exceeds 500 or 550 msec. The possibility that the development of syncope and/or dizziness may be signs of undetected torsades de pointes should be considered, and patients should be instructed to contact a clinician and be evaluated for QT prolongation and potential arrhythmias when such effects occur during sotalol therapy.Because of the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QTc interval.

Sotalol should not be used in patients with hypokalemia or hypomagnesemia until these imbalances are corrected, since such electrolyte abnormalities can exaggerate the degree of QT prolongation and increase the risk of torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients with severe or prolonged diarrhea and in patients receiving diuretics concomitantly. Patients should be advised to report immediately to their clinician conditions, concomitant therapy (e.g., diuretics), and/or manifestations associated with altered electrolyte balance such as severe or prolonged diarrhea, unusual sweating, vomiting, loss of appetite, or thirst. Sotalol also should be administered concomitantly with caution with other drugs known to prolong the QT interval (e.g., class I or other class III antiarrhythmic agents, cisapride, bepridil, phenothiazines, tricyclic antidepressants, certain quinolones [grepafloxacin, sparfloxacin], terfenadine or astemizole [both no longer commercially available in the US]) in patients being treated for ventricular arrhythmias, and such concomitant therapy is not recommended in patients being treated for supraventricular arrhythmias (atrial fibrillation or flutter). In clinical trials in patients with a history of atrial fibrillation or flutter, sotalol was not administered in patients previously treated with oral amiodarone for longer than 1 month in the previous 3 months.

The manufacturer recommends that sotalol be used for the treatment of ventricular or supraventricular arrhythmias only with extreme caution in patients with sick sinus syndrome associated with symptomatic arrhythmias, since the drug may cause sinus bradycardia, pauses, or arrest. In patients being considered for sotalol therapy for supraventricular arrhythmias (atrial fibrillation or flutter), sotalol is contraindicated in those with sick sinus syndrome, unless a functioning pacemaker is present. The risk of torsades de pointes in patients with atrial fibrillation and sinus node dysfunction is increased, especially after cardioversion. Because sotalol has a greater effect in prolonging the QT interval and the action potential duration at lower heart rates (reverse rate dependence), bradycardia following cardioversion in such patients is associated with greater QTc prolongation than observed at higher heart rates.

Sotalol should be used with caution in patients with inadequate cardiac function. Because sympathetic stimulation is necessary to support circulatory function in patients with congestive heart failure, β-blockade with sotalol carries the potential risk of depressing myocardial contractility and precipitating more severe heart failure. Although β-adrenergic blocking agents should be avoided in patients with overt congestive heart failure, sotalol may be administered cautiously, if necessary, in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). However, the fact that sotalol and cardiac glycosides both slow AV conduction also should be considered. Caution also is necessary when initiating sotalol therapy in patients with any evidence of left ventricular dysfunction, although the drug usually is well tolerated hemodynamically.

Since β-adrenergic blocking agents may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic diseases. Sotalol should be used with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema). If sotalol is administered, it is prudent to use the lowest effective dosage to minimize inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of β2-adrenergic receptors.

Signs of hyperthyroidism (e.g., tachycardia) may be masked by sotalol, and patients having or suspected of developing thyrotoxicosis should be monitored closely since abrupt withdrawal of β-adrenergic blockade might precipitate thyroid storm.

It is recommended that sotalol be used with caution in patients with diabetes mellitus (especially those with labile diabetes or those prone to hypoglycemia) since the drug may mask certain signs and symptoms associated with acute hypoglycemia. The drug also should be used with caution in patients with a history of episodic spontaneous hypoglycemia. However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-adrenergic blocking agents.

Sotalol should be used with caution in patients undergoing major surgery involving general anesthesia. The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-adrenergic blocking agents. As with other β-adrenergic blocking agents, the effects of sotalol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol). If patients continue to receive sotalol prior to surgery, particular caution should be employed if anesthetics that depress the myocardium are used (e.g., cyclopropane, ether, trichlorethylene), and the lowest possible dosage of sotalol should be used.

While receiving β-blockers such as sotalol, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated accidental, diagnostic, or therapeutic challenge. These patients may be unresponsive to the usual doses of epinephrine or may develop a paradoxical response to epinephrine when used to treat the reaction.

Abrupt withdrawal of sotalol may exacerbate angina symptoms and/or precipitate myocardial infarction and ventricular arrhythmias in patients with coronary artery disease, or may precipitate thyroid storm in patients with thyrotoxicosis. Therefore, patients receiving sotalol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician. Because coronary artery disease is common and may be undiagnosed, abrupt withdrawal also should be avoided in other patients receiving the drug since such withdrawal could unmask latent coronary insufficiency. When sotalol is discontinued in patients with coronary artery disease or suspected thyrotoxicosis, the patient should be observed carefully; patients with coronary artery disease should be advised to temporarily limit their physical activity. Consideration also should be given to temporary use of another β-blocker if appropriate. If possible, sotalol hydrochloride dosage should be reduced gradually over 1-2 weeks. If exacerbation of angina occurs or acute coronary insufficiency develops after sotalol therapy is interrupted or discontinued, treatment with the drug should be reinstituted promptly, at least temporarily.

Sotalol is contraindicated in patients with bronchial asthma, sinus bradycardia (less than 50 beats per minute during waking hours), second- or third-degree AV block (unless a functioning pacemaker is present), congenital or acquired long-QT syndromes, cardiogenic shock, uncontrolled congestive heart failure, or previous evidence of hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of sotalol in children younger than 18 years of age have not been established. Sotalol has been used in a limited number of infants younger than 3 months of age and children younger than 18 years of age and was effective for the treatment of supraventricular arrhythmias and to a lesser degree for the treatment of ventricular arrhythmias. Mild sinus bradycardia occurred in most of the infants, and fatigue, which required discontinuance in a few patients, occurred in several of the children receiving the drug.

Geriatric Precautions

Safety and efficacy of sotalol in geriatric patients have not been studied specifically to date; however, life-threatening ventricular arrhythmias such as sustained ventricular tachycardia, for which safety and efficacy have been established, occur in many patients older than 50 years of age and clinical trials of sotalol included many such patients. In sotalol clinical trials, the overall risk of cardiac death was associated with increasing age. Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of sotalol-induced toxicity, patients in this age group should be monitored closely and dosage adjusted accordingly.

Mutagenicity and Carcinogenicity

Specific assays to determine the mutagenic or clastogenic potential of sotalol have not been performed to date.

There was no evidence of carcinogenic potential in a 24-month study in rats receiving sotalol hydrochloride dosages of 137-275 mg/kg daily (approximately 30 times the maximum recommended human oral dosage on a mg/kg basis or 5 times the maximum recommended human oral dosage on a mg/m basis). There also was no evidence of carcinogenic potential in a study in mice receiving sotalol hydrochloride dosages of 4141-7122 mg/kg daily (approximately 450-750 times the maximum recommended human oral dosage on a mg/kg basis or 36-63 times the maximum recommended human oral dosage on a mg/m basis).

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits during organogenesis did not reveal any teratogenic potential at sotalol hydrochloride doses that were 100 and 22 times the maximum recommended human oral dose on a mg/kg basis (9 and 7 times the maximum recommended human oral dose on a mg/m basis), respectively. However, higher sotalol hydrochloride dosages of 160 mg/kg daily (16 times the maximum recommended human oral dosage on a mg/kg basis or 6 times the maximum recommended human oral dosage on a mg/m basis) in rabbits were associated with a slight increase in fetal death likely resulting from maternal toxicity. A sotalol hydrochloride dosage of 80 mg/kg daily (8 times the maximum recommended human oral dosage on a mg/kg basis or 3 times the maximum recommended human oral dosage on a mg/m basis) did not produce this effect. An increase in the number of early resorptions was associated with a sotalol hydrochloride dosage of 1000 mg/kg daily in rats (100 times the maximum recommended human oral dosage on a mg/kg basis or 18 times the maximum recommended human oral dosage on a mg/m basis), while no increase was observed at 14 times the maximum recommended human oral dosage on mg/kg basis (2.5 times the maximum recommended human oral dosage on a mg/m basis). Animal data are not always indicative of human response. There are no adequate and well-controlled studies using sotalol in pregnant women, but the drug has been shown to cross the placenta and is found in amniotic fluid. There has been a report of subnormal neonatal birthweight with sotalol. Therefore, sotalol should be used during pregnancy only if the potential benefits justify the possible risks to the fetus.

Fertility

There was no evidence of a reduction in fertility in rats receiving oral sotalol hydrochloride dosages of 1000 mg/kg daily (approximately 100 times the maximum recommended human oral dosage on a mg/kg basis or 9 times the maximum recommended human oral dosage on mg/m basis) prior to mating, except for a small reduction in the number of offspring per litter.

Lactation

Sotalol is distributed into milk, apparently in concentrations approximately 2.5-5.5 times concurrent maternal serum concentrations. Because of the potential for adverse reactions to sotalol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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