Sotalol hydrochloride is a nonselective β-adrenergic blocking agent that exhibits antiarrhythmic activity characteristic of class II and class III antiarrhythmic agents.1, 2, 7, 8, 12, 13, 14, 15, 402, 403, 404
Sotalol is used to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia).1, 4, 5, 6, 7, 8, 11, 12, 26, 400, 401, 402, 403, 404, 405 The drug also is used to maintain normal sinus rhythm in patients with symptomatic atrial fibrillation or flutter who are currently in sinus rhythm.1, 301, 402, 403, 404 Sotalol also has been used in the management of other supraventricular arrhythmias such as paroxysmal supraventricular tachycardia (PSVT)†.300
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.65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 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.65, 67, 68, 70, 71, 72, 73, 74, 75, 76 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.67, 68, 69, 70, 73, 75, 76
Sotalol is used to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia)1, 4, 5, 6, 7, 8, 11, 12, 26, 400, 401, 402, 403, 404, 405 and has been designated an orphan drug by the FDA for such use. 9
Although antiarrhythmic agents, including sotalol, may suppress the recurrence of arrhythmias and improve symptoms, there is no evidence from randomized controlled studies indicating that these drugs have a beneficial effect on mortality or sudden death.1, 405 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 (MI), mild to moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent premature ventricular complexes [PVCs]) who received encainide or flecainide (class I antiarrhythmic drugs) increased substantially compared with placebo.18, 405 (See Cautions in Flecainide 24:04.04.12.) Like other antiarrhythmic agents, sotalol can worsen existing arrhythmias or cause new arrhythmias, including torsades de pointes.1, 3, 4, 7, 8, 12, 14, 402, 403, 404 Because of the drug's arrhythmogenic potential, use of sotalol for less severe arrhythmias, even if symptomatic, is not recommended by the manufacturer,1 and treatment of asymptomatic PVCs should be avoided.1, 3, 4, 7, 8, 12, 14, 402, 403, 404 (See Cautions: Arrhythmogenic Effects.)
Although comparative data are limited, sotalol generally is considered to be as effective as some other antiarrhythmic agents (e.g., procainamide, quinidine) for the management of severe refractory arrhythmias.1, 48, 402, 403, 404, 405 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, and also is effective in patients with less severe arrhythmias.1, 64 Sotalol can reduce PVCs, paired PVCs, and nonsustained ventricular tachycardia in patients with frequent PVCs,1, 7, 11, 12, 402, 403, 404 and can also suppress the recurrence of ventricular tachyarrhythmias in patients with ventricular tachycardia and/or fibrillation.4, 5, 6, 7, 11, 12, 405 The drug also has suppressed Holter monitor evidence of sustained ventricular tachycardia and ventricular tachycardia induced by programmed electrical stimulation (PES).1, 4, 6, 7, 11, 12 Although some studies have shown that sotalol may 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,11, 12 the effect of the drug on survival (e.g., relative to placebo) remains to be established.1
Life-threatening Ventricular Arrhythmias During Cardiac Arrest
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.400 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.400, 401 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.400, 401 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.400, 401 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias, in Epinephrine 12:12.12.) 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).400, 401 IV sotalol may be used for the management of hemodynamically stable sustained monomorphic ventricular tachycardia during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for adult tachycardia.400, 401, 405
Sotalol appears to be effective in the suppression and prevention of various supraventricular tachycardias (SVTs), including atrial fibrillation or flutter and PSVT†.1, 64, 300, 301, 402, 403, 404 Because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents such as sotalol generally should be reserved for patients who are not candidates for catheter ablation and who do not respond to or cannot be treated with AV nodal blocking agents (i.e., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents).300, 401
Atrial Fibrillation and Flutter
Sotalol is used to maintain normal sinus rhythm in patients with symptomatic atrial fibrillation or flutter who are currently in sinus rhythm.1, 301, 402, 403, 404 Because of the potential to cause life-threatening ventricular arrhythmias, the manufacturer states that sotalol should be reserved for the treatment of highly symptomatic atrial fibrillation/flutter.1, 42, 51, 56, 57, 402, 403, 404 (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.1, 402, 403, 404
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.43, 44, 45, 47, 301 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.47
Other Supraventricular Tachycardias
Sotalol also has been used in patients with other SVTs, including PSVT due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT).†64, 300 However, vagal maneuvers and IV adenosine generally are preferred for initial treatment of PSVT in patients without contraindications.300 Sotalol may be a reasonable choice of therapy for the ongoing management of symptomatic SVT in patients 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.300
Sotalol hydrochloride is administered orally or by IV infusion when oral administration is not feasible.1, 402, 403, 404
Because of the arrhythmogenic potential of sotalol, initiation or reinitiation of therapy, or conversion from IV to oral therapy should be performed in a facility capable of providing cardiac resuscitation, continuous electrocardiogram (ECG) monitoring, and calculation of creatinine clearance; treatment should be initiated in the presence of personnel trained in the management of serious arrhythmias.1, 7, 8, 42, 48, 402, 403, 404 Patients should be closely monitored for at least 3 days (or until steady-state plasma concentrations are achieved) whenever treatment is initiated or dosage is increased.1, 402, 403, 404 Prior to initiating therapy, the patient's baseline QT interval and creatinine clearance should be determined; therapy should not be initiated if the QT interval corrected for rate (QTc) exceeds 450 msec or creatinine clearance is less than 40 mL/minute.1, 402, 403, 404 Because the potential for arrhythmogenic events increases with increasing dosage, patients should be monitored closely during the dose titration phase until steady-state concentrations are reached.1, 3, 4, 7, 47, 402, 403, 404 When titrating dosage, QT interval should be determined 2-4 hours after each dose increase (if the drug is given orally) or after completion of each IV infusion; dose should be reduced, dosing interval increased, or therapy discontinued if prolongation of the QT interval to 500 msec or greater occurs.1, 402, 403, 404
Patients should be advised not to discontinue or interrupt sotalol therapy without consulting their clinician.1, 403, 404 Patients should be given an adequate supply of the drug upon hospital discharge to allow uninterrupted therapy until their outpatient prescription can be filled.1, 403, 404
Patients with atrial fibrillation should be anticoagulated according to usual medical practice.402 (See Uses: Embolism Associated with Atrial Fibrillation in Warfarin 20:12.04.08.)
Sotalol hydrochloride is administered orally as tablets or oral solution.1, 403, 404
If the drug is administered as an oral solution, the commercially available oral solution containing 25 mg/5 mL may be used or an oral solution may be extemporaneously prepared by adding five 120-mg tablets to a 180-mL polyethylene terephthalate (PET) prescription bottle containing 120 mL of simple syrup with 0.1% sodium benzoate (syrup NF); alternatively, the syrup may be added to the tablets.1, 404 An oversized bottle is used to allow more effective shaking of the mixture.1, 403, 404 The tablets may be added intact to the syrup or crushed; if crushed, care should be taken to transfer the entire quantity of tablet powder to the syrup.1, 404 The mixture should be shaken to wet the tablets and the tablets allowed to hydrate for at least 2 hours.1, 404 The bottle should then be shaken intermittently over another 2 hours until dispersion of fine particles is obtained; alternatively, the tablets may be allowed to hydrate overnight to simplify the disintegration process.1, 404 An appropriate measuring device (e.g., oral dosing syringe) should be used to administer oral solutions of sotalol; use of a teaspoon or tablespoon may result in dosing errors and is not recommended.403
Administration of oral sotalol 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 concentrations and area under the plasma concentration-time curve (AUC), respectively, of the drug.1, 403, 404 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.1
Sotalol hydrochloride is administered by IV infusion over 5 hours using a volumetric pump to ensure that the drug is delivered at a constant rate.402
The commercially available 15-mg/mL injection concentrate must be diluted with a suitable diluent (i.e., 0.9% sodium chloride injection, 5% dextrose injection, lactated Ringer's injection) prior to administration.402 The manufacturer recommends that the volume of injection concentrate used to prepare the infusion solution and the final infusion solution volume exceed those required for the intended dose to account for the volume loss in the dead space of the infusion set.402 Preparation of a final volume of 120 or 300 mL is recommended; however, the actual volume that should be infused is 100 or 250 mL, respectively.402 For a dose of 75 mg, the manufacturer recommends that 6 mL of the injection concentrate be diluted with 114 or 294 mL of diluent to prepare a final volume of 120 or 300 mL, respectively.402 For a dose of 112.5 mg, the manufacturer recommends that 9 mL of the injection concentrate be diluted with 111 or 291 mL of diluent to prepare a final volume of 120 or 300 mL, respectively.402 For a dose of 150 mg, the manufacturer recommends that 12 mL of injection concentrate be diluted with 108 or 288 mL of diluent to prepare a final volume of 120 or 300 mL, respectively.402
Dosage of sotalol hydrochloride must be adjusted carefully according to individual requirements and response, patient tolerance, renal function, and QT interval.1, 4, 8, 402, 403, 404
Appropriate dosage adjustments should be made for patients with impaired renal function to minimize the risk of drug accumulation and arrhythmogenic events.1, 402, 403, 404 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) If a dose is missed, patients should be advised to take the next dose at the regularly scheduled time and to not take a double dose or increase the dosing frequency to compensate for the missed dose.1, 403, 404
Life-threatening Ventricular Arrhythmias
For the management of life-threatening ventricular arrhythmias in adults with normal renal function (creatinine clearance exceeding 60 mL/minute), an initial oral sotalol hydrochloride dosage of 80 mg twice daily is recommended.1, 403, 404, 405 Dosage may be increased every 3 days in increments of 80 mg daily provided QTc does not exceed 500 msec.1, 403, 404 The usual oral maintenance dosage in adults is 160-320 mg daily, given in 2 or 3 divided doses; because of the long elimination half-life of the drug, dosing more than 2 times a day usually is not necessary.1, 404 In patients with life-threatening refractory ventricular arrhythmias, oral sotalol hydrochloride dosages as high as 480-640 mg daily have been used; however, the risk of serious arrhythmias increases with higher dosages.1, 8, 403, 404
For maintenance of normal sinus rhythm in adults with atrial fibrillation or flutter who have normal renal function (creatinine clearance exceeding 60 mL/minute), an initial oral sotalol hydrochloride dosage of 80 mg twice daily is recommended.1, 42, 61, 403, 404 Dosage may be increased every 3 days in increments of 80 mg daily provided QTc does not exceed 500 msec.1, 403, 404 In a dose-response study, the most effective dosage in preventing recurrence of atrial fibrillation or flutter was 120 mg once or twice daily.1, 42, 45, 403, 404 Some clinicians state that dosage may be increased up to a maximum of 160 mg twice daily (provided the drug is well tolerated without excessive QT interval prolongation) if patients continue to experience recurrences of symptomatic atrial fibrillation or flutter.26, 47, 50, 403
When oral therapy is not feasible, sotalol may be administered as an IV infusion.402 Because oral bioavailability of sotalol is 90-100%, equivalent IV doses are lower than oral doses.402 The manufacturer recommends the following dose equivalencies when converting between oral and IV dosing: 75 mg IV for an oral dose of 80 mg, 112.5 mg IV for an oral dose of 120 mg, and 150 mg IV for an oral dose of 160 mg.402
Life-threatening Ventricular Arrhythmias
The recommended initial IV dosage of sotalol hydrochloride for the management of life-threatening ventricular arrhythmias in adults is 75 mg once or twice daily (depending on creatinine clearance) by IV infusion over 5 hours.402, 405 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) If the desired response has not been achieved and the drug is well tolerated without excessive QT interval prolongation, dosage may be increased to 112.5 mg once or twice daily (depending on creatinine clearance); the manufacturer recommends that dosage be increased in increments of 75 mg daily every 3 days.402 Based on experience with oral sotalol hydrochloride, the usual therapeutic effect should be observed with IV dosages of 75-150 mg once or twice daily; however, patients with life-threatening refractory ventricular arrhythmias have received higher dosages (e.g., oral dosages of 240-320 mg once or twice daily corresponding to IV dosages of 225-300 mg once or twice daily).402
The recommended initial IV dosage of sotalol hydrochloride for the maintenance of normal sinus rhythm in adults with atrial fibrillation or flutter is 75 mg once or twice daily (depending on creatinine clearance) by IV infusion over 5 hours.402 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) If the desired response has not been achieved and the drug is well tolerated without excessive QT interval prolongation, dosage may be increased after at least 3 days to 112.5 mg once or twice daily (depending on creatinine clearance).402 Based on experience with oral sotalol hydrochloride, the usual therapeutic effect should be observed with an IV dosage of 112.5 mg once or twice daily; however, the manufacturer states that IV dosage may be increased up to 150 mg once or twice daily if necessary provided the drug is well tolerated.402
Dosage of sotalol hydrochloride in pediatric patients is based on pharmacokinetic data.1, 402, 403, 404 (See Cautions: Pediatric Precautions.) The usual precautions observed in adults should also be taken when initiating or reinitiating therapy in pediatric patients.1, 402, 403, 404 Dosage increases should preferably be performed in an inpatient setting where patients can be closely monitored.1 Because sotalol has similar potency in children and adults, dosages used in pediatric patients should achieve plasma concentrations similar to those within the adult dosage ran however, dosage should be individualized based on clinical response, heart rate, and QTc.1, 402, 404 There are no studies of IV sotalol hydrochloride in pediatric patients.402
The recommended initial oral dosage of sotalol hydrochloride for the management of ventricular arrhythmias or atrial fibrillation/flutter in children about 2 years of age or older with normal renal function is 30 mg/m2 3 times daily (total daily dose of 90 mg/m2); dosage may be increased up to a maximum of 60 mg/m2 3 times daily, allowing at least 36 hours to elapse between dosage escalations to achieve steady-state concentrations.1, 402, 403, 404
Dosage of sotalol hydrochloride in children about 2 years of age or younger should be reduced from the usual oral dosage for older children (i.e., 30 mg/m2 3 times daily) by an age-dependent factor obtained from the manufacturer's prescribing information.1, 402, 403, 404 The age-dependent factor is approximately 0.3 in neonates about 1 week old, 0.68 in infants 1 month of age, and 0.97 in infants 20 months of age.1, 402, 403, 404 The calculated dose after multiplying the age-dependent factor by 30 mg/m2 is 9 mg/m2 in neonates about 1 week old, 20 mg/m2 in infants 1 month of age, and 29.1 mg/m2 in infants 20 months of age, administered 3 times daily.1, 402, 403
Use of sotalol in pediatric patients with renal impairment has not been evaluated; in general, lower doses should be used or the dosing interval should be increased.1, 402, 403, 404
Conversion from other Antiarrhythmic Agents
The manufacturer recommends a transition period when converting patients from another antiarrhythmic agent to sotalol therapy.1, 404 In general, initiation of sotalol therapy should be delayed for a period of at least 2-3 elimination half-lives of the previously administered antiarrhythmic; the patient should be monitored carefully during the transition.1, 404 404 Class I or Class III antiarrhythmic agents should be withheld for at least 3 half-lives prior to dosing with sotalol hydrochloride.1, 402, 403, 404
Dosage in Renal and Hepatic Impairment
In patients with renal impairment, the dose or dosing frequency of sotalol hydrochloride should be reduced to minimize the risk of proarrhythmia; as in patients with normal renal function, QT interval and heart rate should be closely monitored.1, 26, 402, 403, 404 (See Cautions: Arrhythmogenic Effects.) Dosing interval should be modified according to the patient's estimated creatinine clearance.1, 402, 403, 404 In general, the initial oral adult sotalol hydrochloride dose of 80 mg and subsequent doses should be administered twice daily in patients with a creatinine clearance greater than 60 mL/minute and once daily in patients with a creatinine clearance of 40-60 mL/minute.402, 403 The drug is generally contraindicated in patients with creatinine clearance less than 40 mL/minute.1, 402, 403, 404 In patients with ventricular arrhythmias, some manufacturers recommend a dosing interval of 36-48 hours in adults with creatinine clearance of 10-29 mL/minute and individualized dosing in those with creatinine clearance less than 10 mL/minute.1, 404 Since terminal elimination half-life of the drug is prolonged in patients with renal impairment, dosage increases generally should be made after administration of at least 5 doses at appropriate intervals.1, 8, 404 Sotalol is partially removed by dialysis; however, the manufacturers make no dosing recommendations for patients undergoing dialysis.1, 404 Dosage of sotalol hydrochloride in children with renal impairment has not been established; however, reduced doses and increased dosing intervals are recommended in patients of all age groups with renal impairment.1, 404
The manufacturer states that clearance of sotalol is not altered by impaired hepatic function.1, 402, 403, 404
Sotalol shares the toxic potentials of nonselective β-adrenergic blocking agents1, 3, 4, 6, 8, 28, 404 and, in therapeutic dosage, generally is well tolerated during long-term therapy.3, 4, 8, 28, 48 However, as a class III antiarrhythmic agent (see Description), sotalol, unlike conventional β-blockers, can prolong the QT interval and precipitate torsades de pointes.1, 3, 4, 8, 12, 14, 28, 301, 402, 403, 404 Adverse effects associated with sotalol are generally dose related and typically result from the drug's class II (beta-blocking) and class III (cardiac action potential duration prolongation) effects.1, 404
The most serious adverse effect of sotalol is torsades de pointes,1, 3, 4, 8, 28, 404 which occurred in almost 4 or 1% of patients with a history of sustained ventricular tachycardia or other less serious ventricular arrhythmias, respectively, who received the drug orally in clinical studies.1, 28, 404 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.1, 404 The most common adverse effects resulting in discontinuance of the drug include effects usually associated with β-blockade.6, 8, 11, 28 Fatigue caused discontinuance of sotalol in 4-5% of patients,1, 28, 404 bradycardia (heart rate less than 50 bpm) in 2-3%,1, 28, 404 dyspnea in 2-3%,1, 28, 404 arrhythmogenic effects in 1.5-3%,1, 404 asthenia in 2%,1, 404 and dizziness in 2% of patients receiving the drug in clinical trials.1, 404 Overall, discontinuance of sotalol as a result of adverse effects occurred in 17% of patients receiving the drug in clinical trials and in 10% of those treated for at least 2 weeks.1, 404 Abrupt withdrawal of sotalol should be avoided, especially in patients with coronary artery disease, since it may exacerbate angina or precipitate myocardial infarction (MI).1, 404
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; the arrhythmogenic potential is the most serious risk associated with the drug.1, 3, 8, 28, 47, 404 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,1, 6, 8, 28, 404 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.1, 402, 404 The risk of torsades de pointes increases progressively with prolongation of the QT interval1, 404 and is worsened by a reduction in heart rate and serum potassium concentration.1, 3 (See Cautions: Precautions and Contraindications.)
In patients with a history of sustained ventricular tachycardia, the frequency of torsades de pointes was 4% and the frequency of worsened ventricular tachycardia was about 1%; in patients with other, less serious ventricular arrhythmias, the frequency of torsades de pointes was 1% and the frequency of new or worsened ventricular tachycardia was 0.7%.1
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.8 Overall, cardiac death was associated with low left ventricular ejection fraction, history of congestive heart failure and/or cardiomegaly, and increasing a 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.8 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.8 A clear relationship between sotalol dosage and the frequency of death has not been demonstrated to date.8
Prolongation of the QTc interval and the occurrence of torsades de pointes are dose related.1, 404 In patients with sustained ventricular tachycardia or ventricular fibrillation, the incidence 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.1, 28, 404 The frequency of torsades de pointes in patients with 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.1, 404 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 heart failure.1, 47, 50, 404 Patients with sustained ventricular tachycardia and a history of heart failure appeared to be at greatest risk of a serious arrhythmogenic event, with an occurrence rate of 7%.50, 402 Approximately two-thirds of patients experiencing sotalol-induced torsades de pointes reverted spontaneously to their baseline rhythm.402 The remaining patients required either cardioversion or overdrive pacing or treatment with other drugs.3, 402 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.47, 402 Most cases of torsades de pointes required discontinuance of sotalol therapy, but 17% of patients continued the drug at a lower dosage.402 Sotalol should be used with particular caution if the QTc interval exceeds 500 msec during treatment, and dosage reduction or discontinuance of the drug should be seriously considered when the QTc interval exceeds 500 msec.1, 28 Regardless of the QTc interval, caution should be exercised because of the multiple risk factors associated with torsades de pointes.1, 402, 404
Sotalol-induced arrhythmogenic events can occur not only when initiating therapy, but with every upward dosage adjustment.1, 3, 4, 7, 8, 28, 45, 47, 404 About 75% of such serious events (e.g., torsades de pointes, worsened ventricular tachycardia) occur within 7 days of initiating therapy with the drug,4, 28 and about 60% occur within 3 days of initiation of the drug or dosage adjustment.8, 28 Initiation of sotalol therapy at low dosages with gradual upward titration and appropriate monitoring should reduce the risk of arrhythmogenic events.1, 404 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 recommends1, 404 that both initiation and reinitiation of sotalol therapy and any subsequent upward dosage adjustments be performed in an institutional setting.1, 7, 8, 404
Sympathetic stimulation is necessary for supporting circulatory function in heart failure.402 Therefore, because of its β-adrenergic blocking effects, sotalol may cause or worsen heart failure,1, 3, 4, 5, 8, 28, 404 particularly in patients with preexisting heart failure (New York Heart Association [NYHA] class II-IV)8, 28 or sustained ventricular tachycardia or ventricular fibrillation,8, 28 and/or a history of cardiomegaly,8, 28 cardiomyopathy,8, 28 coronary artery disease,8, 28 or myocardial infarction.8 The effect of these risk factors appears to be cumulative, with patients exhibiting more risk factors being at greater risk for precipitated or worsened heart failure during therapy with the drug.8
New or worsened heart failure occurred in 3% of patients receiving sotalol in premarketing studies and required discontinuance of the drug in about 1% of patients.8, 402 The frequency of new or worsened heart failure was 5% in patients with sustained ventricular tachycardia or ventricular fibrillation and 7% in patients with a history of heart failure.402 In patients with sustained ventricular tachycardia or ventricular fibrillation, the most reliable predictive risk factors were a history of congestive heart failure or cardiomegaly.8 The 1-year frequency of new or worsened heart failure was 3% in patients without a previous history and 10% in those with a previous history of heart failure.402 The risk of new or worsened heart failure was closely related to NYHA classification.8, 28 The occurrence of heart failure was not related to dosage of sotalol,8, 28 regardless of heart failure history.8 New or worsened heart failure occurred in 2.7% of patients with nonsustained ventricular tachycardia or premature ventricular complexes (PVCs) and in 2.3% of patients with supraventricular arrhythmias.8
Chest pain and palpitation 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.402 In pooled data from several clinical trials in a limited number of patients with atrial fibrillation or flutter, angina pectoris occurred in 1.6-2% of patients receiving sotalol hydrochloride 160-320 mg daily.402 Nonanginal chest pain occurred in 2.5-4.6% of these patients.402 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.402 Hypotension was reported in 6% of patients with a history of ventricular arrhythmias and required discontinuance in 2% of patients.402 Presyncope was reported in 4%;402 peripheral vascular disorder, cardiovascular disorder, vasodilation, or AICD discharge in 3%;402 and hypertension in 2% of patients with a history of ventricular arrhythmias receiving sotalol,402 and each of these adverse effects required discontinuance of the drug in less than 1% of patients.402
Sinus bradycardia (heart rate less than 50 bpm),1, 3, 4, 5, 28, 402, 404 which increases the risk of torsades de pointes,1, 402, 404 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 2.4% of patients.402 Pooled data from several clinical trials in patients with atrial fibrillation or flutter indicate that bradycardia 42, 47, 402 occurred in 12-13% of patients receiving oral sotalol; discontinuance of therapy was required in 2.4% of these patients.402 Sinus pause, arrest, and nodal dysfunction occurred in less than 1% of patients, and second- or third-degree AV block occurred in about 1% of patients receiving sotalol.1
QRS intervals are affected minimally by sotalol;1, 6, 8, 11, 402 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.1 Excessive prolongation of the QT interval (to greater than 550 msec) can promote serious arrhythmias and should be avoided during sotalol therapy.1 (See Cautions: Arrhythmogenic Effects.)
Fatigue, dizziness, and asthenia, which appear to be dose related,1 are the most common adverse nervous system effects of sotalol,1, 3, 28, 404 occurring in 20% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving the drug in clinical trials.402 Fatigue and dizziness1, 402 also are the most common adverse nervous system effects of sotalol in patients with a history of atrial fibrillation or flutter, occurring in 18.9-19.6 or 13.1-16.3% of these patients, respectively.1, 402 Fatigue resulted in discontinuance of sotalol in 4.6% of patients with a history of these supraventricular arrhythmias.402 Lightheadedness, dizziness, and syncope also are symptoms of torsades de pointes.47, 55, 58, 60 Asthenia1, 3, 28 and lightheadedness were reported in 13 and 12%, respectively, of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials.402 Weakness was reported in about 5% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.1, 402 Headache3, 5 and sleep disturbances5 were reported in 8% of patients with ventricular arrhythmias receiving sotalol and required discontinuance in less than 1% of patients.402 Insomnia was reported in 2.6-4.1% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.402 Perspiration was reported in 6% of patients;402 altered consciousness,402 depression,5, 402 paresthesia,5, 402 or anxiety402 in 4% of patients;402 and localized pain,402 mood change,402 or appetite disorder402 in 3% of patients with a history of ventricular arrhythmias receiving sotalol in clinical trials;402 each of these adverse effects required discontinuance of the drug in less than 1% of patients.402 Cold sensation was reported in 2-2.5% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.402 Rarely, emotional lability, slightly clouded sensorium, incoordination, vertigo, and paralysis have been reported during postmarketing experience.1 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.1, 402
Dyspnea was reported in 21% of patients with sustained ventricular tachycardia or ventricular fibrillation receiving the drug in clinical trials but required discontinuance of therapy in only 2% of patients.402 Dyspnea1, 42 also has 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.1, 402 Pulmonary problems4 were reported in 8%,402 upper respiratory tract problems402 in 5%,402 and asthma402 in 2% of patients with ventricular arrhythmias receiving sotalol;402 each of these adverse effects required discontinuance of therapy in less than 1% of patients.402 Influenza or upper respiratory tract infection has been reported in 0.8-2 or 2.6-3.3%, respectively, of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.402 Cough or tracheobronchitis has been reported in 2.5-3.3 or 0.7-3.3%, respectively, of patients with a history of these supraventricular arrhythmias receiving sotalol in clinical trials.402 Rarely, pulmonary edema has been reported during postmarketing experience with the drug.1, 402 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;1, 8, 402 such changes may be clinically important in patients with underlying airway disease.1, 402 (See Cautions: Precautions and Contraindications.)
Nausea and vomiting are the most frequent adverse GI effects of sotalol,1, 3, 402 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, respectively, receiving the drug in clinical trials and requiring discontinuance in up to 1% of patients.1, 402 Other adverse GI effects each required discontinuance of sotalol in less than 1% of patients with ventricular arrhythmias.402 Diarrhea3 and dyspepsia were reported in 7 and 6%, respectively, of patients with ventricular arrhythmias receiving sotalol in clinical trials.402 Diarrhea or dyspepsia was reported in 5.2-5.7 or 2-2.5% of patients, respectively, with a history of atrial fibrillation or flutter receiving sotalol in controlled clinical trials.1 Abdominal pain and colon problems occurred in 3% of patients, and flatulence occurred in 2% of patients with ventricular arrhythmias.402 Abdominal pain or abdominal distension was reported in 2.5-3.9% or 0.7-2.5%, respectively, of patients with a history of atrial fibrillation or flutter receiving sotalol in controlled clinical trials.1, 402
Increased serum concentrations of hepatic enzymes have occurred occasionally with sotalol therapy,4, 402 but a causal relationship to the drug has not been established.402
Genitourinary disorders and sexual dysfunction were reported in 3 and 2%, respectively, of patients with ventricular arrhythmias receiving sotalol in clinical trials and each required discontinuance of the drug in less than 1% of patients.402
Extremity pain and back pain were reported in 7 and 3%, respectively, of patients with ventricular arrhythmias receiving sotalol in clinical trials and each required discontinuance of the drug in less than 1% of patients.402 Rarely, myalgia has been reported during postmarketing experience with the drug.1, 402 Musculoskeletal pain or musculoskeletal chest pain has been reported in 2.6-4.1 or 2-2.5%, respectively, of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.402
Rash was reported in 5% of patients with ventricular arrhythmias receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients.402 Rarely, photosensitivity reactions, pruritus, and alopecia have been reported during postmarketing experience with the drug.402 Hyperhidrosis has been reported in 4.9-5.2% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.1, 402
Bleeding was reported in 2% of patients with ventricular arrhythmias receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients.402 Rarely, thrombocytopenia, leukopenia, and eosinophilia have been reported during postmarketing experience with the drug.1, 402
Visual disorders5, 402 were reported in 5% of patients with ventricular arrhythmias receiving sotalol in clinical trials and required discontinuance of the drug in less than 1% of patients.402 Visual disturbances were reported in 0.8-2.6% of patients with a history of atrial fibrillation or flutter receiving sotalol in clinical trials.402
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.402 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.402 Increases in blood glucose concentration and insulin requirements can occur in patients with diabetes mellitus receiving sotalol.1, 402, 404 Rarely, hyperlipidemia has been reported during postmarketing experience with the drug.1, 402
Precautions and Contraindications
Sotalol shares the toxic potentials of other nonselective β-adrenergic blocking agents,1, 3, 4, 5, 6, 7, 8, 402, 403, 404 and the usual precautions of these agents should be observed.1, 8, 404 In addition, as a class III antiarrhythmic agent, sotalol, unlike conventional β-blockers, can precipitate torsades de pointes.1, 12, 14, 404
Sotalol, like other antiarrhythmics, has been associated with the development or exacerbation of arrhythmias in some patients.1, 3, 8, 28, 404 (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 the postmarketing Cardiac Arrhythmia Suppression Trial (CAST).17, 18, 19, 20, 21 Findings from the CAST study after an average of 10 months of follow-up indicated that the rate of total mortality and nonfatal cardiac arrest in patients with recent MI, mild-to-moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent PVCs) who received encainide or flecainide was increased substantially.17, 18, 19, 20, 21 (For additional information on the CAST study, see Cautions, in Flecainide 24:04.04.12.)
While sotalol can be used safely and effectively in the chronic management of life-threatening ventricular arrhythmias following MI, experience with the drug in the management of arrhythmias during the early phase of recovery from an acute MI 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.1 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), double-blind, placebo-controlled secondary prevention trial in patients with recent MI (but not necessarily concurrent ventricular arrhythmias).1, 10, 402, 404 However, in patients who received an initial (i.e., not titrated) dosage of 320 mg daily in the study and in high-risk postinfarction patients who received high dosages (320 mg twice daily) in another smaller study, there was some evidence of a possible excess in early (within 2 weeks) sudden deaths.1, 402, 404 Therefore, sotalol should be used cautiously and with careful titration of dosage if the drug is used during the first 2 weeks following an acute MI, particularly in patients with markedly impaired ventricular function.402 Although specific studies of sotalol in treating supraventricular arrhythmias after a recent MI have not been performed to date, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia, or prolonged QT interval apply.1, 402, 404
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.1, 404 (See Cautions: Arrhythmogenic Effects.) Arrhythmogenic events must be anticipated not only when sotalol therapy is initiated, but also with each upward dosage titration.1, 404 To minimize the risk of arrhythmogenic effects, the recommendations for initiation of sotalol therapy and dosage adjustments should be closely followed.1, 404 (See Dosage and Administration.) In addition, excessive accumulation of the drug in patients with diminished renal function should be avoided with appropriate dosage adjustment.1, 404 Because of the arrhythmogenic potential, the manufacturer1, 404 recommends that patients be hospitalized for a minimum of 3 days (or until steady-state concentrations are achieved) for initiation or reinitiation of sotalol therapy in a facility capable of providing cardiac resuscitation and continuous ECG monitoring.1, 7, 8, 404
Sotalol increases QTc interval in a dose-related fashion and thereby increases the risk of torsades de pointes.1, 404 Therefore, the QT interval should be monitored during therapy and dosage adjusted accordingly.1, 404 (See Dosage and Administration: Administration.) Sotalol should not be initiated in patients with a QT interval exceeding 450 msec.1, 404 If the QT interval exceeds 500 msec, the dose should be reduced, the dosing interval increased, or the drug should be discontinued.1, 402, 403, 404 Excessive prolongation of the QT interval (to greater than 500 msec) can promote serious arrhythmias and should be avoided during sotalol therapy.1, 404 The possibility that the development of syncope and/or dizziness may be signs of undetected torsades de pointes should be considered.55, 58, 60 Because of the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QTc interval.1, 404
Sotalol should not be used in patients with hypokalemia or hypomagnesemia until these imbalances are corrected,1, 42, 45, 48, 404 since such electrolyte abnormalities can exaggerate the degree of QT prolongation and increase the risk of torsades de pointes.1, 3, 404 Special attention should be given to electrolyte and acid-base balance in patients with severe or prolonged diarrhea and in patients receiving diuretics concomitantly.1, 45, 47, 50, 404 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.1, 404 Sotalol generally should not be used concomitantly with other drugs known to prolong the QT interval (e.g., class I or other class III antiarrhythmic agents, certain oral macrolides [e.g., azithromycin, clarithromycin], phenothiazines, tricyclic antidepressants, certain quinolones [e.g., ciprofloxacin, levofloxacin]).1, 42, 404, 405 The manufacturers state that class Ia antiarrhythmic agents such as disopyramide, quinidine, and procainamide and class III antiarrhythmic agents such as amiodarone should not be used concomitantly with sotalol and should be discontinued for at least 3 half-lives prior to dosing with sotalol.1, 404 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.1, 42, 404 There is only limited experience with concomitant use of class Ib or Ic antiarrhythmics and sotalol.1 The manufacturers state that additive class II effects should be anticipated with the use of other β-blocking agents concomitantly with sotalol.1, 404
Sotalol is contraindicated in patients with sinus bradycardia, second- or third-degree AV block, or sick sinus syndrome, unless a functioning pacemaker is present.1, 402, 403, 404 The risk of torsades de pointes in patients with atrial fibrillation and sinus node dysfunction is increased, especially after cardioversion.49, 50, 402, 403 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.1, 48, 49, 52, 404
Sotalol should be used with caution in patients with inadequate cardiac function.1, 404 Because sympathetic stimulation is necessary to support circulatory function in patients with heart failure, β-blockade with sotalol carries the potential risk of depressing myocardial contractility and precipitating more severe heart failure.402 However, the fact that sotalol and cardiac glycosides both slow AV conduction also should be considered.1
Since β-adrenergic blocking agents may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic diseases.1, 403, 404 Use of sotalol is not recommended in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema).1, 402, 403, 404 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.1, 402, 403, 404
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 (e.g., tachycardia).1, 402, 403, 404 Sotalol may increase blood glucose concentrations and insulin requirements in diabetic patients.1, 402, 403, 404 The drug also should be used with caution in patients with a history of episodic spontaneous hypoglycemia.403 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.40
There is some controversy regarding the perioperative use of β-adrenergic blocking agents.34, 402 Severe, protracted hypotension, bradycardia, and stroke have occurred during surgery in some patients who have received β-adrenergic blocking agents; in addition, it is unclear whether such use confers any mortality benefit or risk.34, 35, 402 It is generally recommended that β-blockers be continued during surgery in patients who are already receiving these drugs for a chronic condition.1, 34, 404 However, the risks versus benefits should be carefully considered in individual patients.1, 34, 404
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.1, 404 These patients may be unresponsive to the usual doses of epinephrine used to treat the reaction.1, 402, 403, 404
Abrupt withdrawal of sotalol may exacerbate angina symptoms and/or precipitate MI in patients with ischemic heart disease, or may precipitate thyroid storm (since signs of hyperthyroidism such as tachycardia may be masked by the drug) in patients with thyroid disease.1, 402, 403, 404 Therefore, patients receiving sotalol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician.1, 402, 403, 404 If possible, sotalol hydrochloride dosage should be reduced gradually and with close monitoring over 1-2 weeks, especially in patients with ischemic heart disease.1, 402, 403, 404 If exacerbation of angina occurs or acute coronary insufficiency develops after sotalol therapy is interrupted or discontinued, appropriate treatment (e.g., temporary use of another β-blocker) should be instituted.1, 403, 404
Sotalol reduces systolic and diastolic blood pressures and may result in hypotension.1, 402, 403, 404 Hemodynamic monitoring is recommended in patients with marginal cardiac compensation.1, 402, 403, 404
Sotalol is contraindicated in patients with bronchial asthma or related bronchospastic conditions,1, 402, 403, 404 sinus bradycardia (less than 50 beats per minute during waking hours),1, 402, 403, 404 second- or third-degree AV block (unless a functioning pacemaker is present),1 congenital or acquired long-QT syndromes,1, 402, 403, 404 cardiogenic shock,1, 402, 403, 404 decompensated heart failure,1, 402, 403, 404 hypokalemia (serum potassium concentrations less than 4 mEq/L),1, 402, 403, 404 or hypersensitivity to the drug.1, 402, 403, 404 In addition, sotalol is contraindicated for the treatment of atrial fibrillation or flutter in patients with baseline QT interval exceeding 450 msec and in patients with creatinine clearance less than 40 mL/minute.1, 404
Safety and efficacy of sotalol in children younger than 18 years of age1, 26, 404 have not been established.1, 404 Sotalol has been used in a limited number of infants younger than 3 months of age1, 29, 30, 404 and children younger than 18 years of age1, 30, 404 and was effective for the treatment of supraventricular arrhythmias29, 30 and to a lesser degree for the treatment of ventricular arrhythmias.30 Mild sinus bradycardia occurred in most of the infants,29 and fatigue, which required discontinuance in a few patients, occurred in several of the children receiving the drug.30 The physiologic effects and pharmacokinetics of sotalol have been evaluated in infants and children 3 days to 12 years of age.1 Dosage recommendations in pediatric patients are based on pharmacokinetic data.1 Similar to adults, serious adverse events including death, torsades de pointes, other proarrhythmias, AV block, and bradycardia have been reported in infants and children; therefore, the usual precautions in adults should also be observed when sotalol is used in pediatric patients.1, 402
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.3, 4, 5, 6, 8 In sotalol clinical trials, the overall risk of cardiac death was associated with increasing age.8 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.1, 403
Mutagenicity and Carcinogenicity
Specific assays to determine the mutagenic or clastogenic potential of sotalol have not been performed to date.1, 402, 403, 404
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/m2 basis).1, 402, 403, 404 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/m2 basis).1, 402, 403, 404
Pregnancy, Fertility, and Lactation
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/m2 basis), respectively.1, 404 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/m2 basis) in rabbits were associated with a slight increase in fetal death likely resulting from maternal toxicity.1, 404 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/m2 basis) did not produce this effect.1, 404 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/m2 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/m2 basis).1, 404 Animal data are not always indicative of human response.1, 404 There are no adequate and well-controlled studies using sotalol in pregnant women,1, 404 but the drug has been shown to cross the placenta1, 31, 32 and is found in amniotic fluid.1, 404
Sotalol is distributed into milk,1, 31, 32, 33, 402, 403, 404 apparently in concentrations approximately 2.5-5.5 times concurrent maternal serum concentrations.31, 32, 33 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.1, 402, 403, 404
Sotalol hydrochloride (MJ 1999) is a nonselective β-adrenergic blocking agent.1, 2, 7, 8, 11, 12 Like propranolol, sotalol inhibits response to adrenergic stimuli by competitively blocking β1-adrenergic receptors within the myocardium and β2-adrenergic receptors within bronchial and vascular smooth muscle.2, 7, 8 In addition, sotalol, like propranolol, exhibits antiarrhythmic activity characteristic of class II antiarrhythmic agents.1, 2, 7, 8, 404 However, unlike propranolol, sotalol does not exhibit membrane-stabilizing activity1, 8 but, as a methanesulfonanilide derivative, does exhibit electrophysiologic effects characteristic of class III antiarrhythmic agents (e.g., prolongs repolarization and refractoriness without affecting conduction).1, 2, 7, 8, 12, 13, 14, 15 Sotalol does not exhibit intrinsic sympathomimetic activity.8
The electrophysiologic effects of sotalol, like other methanesulfonanilide derivatives, also differ from those of many other commonly used antiarrhythmics (e.g., class I agents).2, 12, 13, 14, 15 In vitro studies suggest that sotalol selectively inhibits the rapidly activating component of the potassium channel involved in repolarization of cardiac cells (i.e., the rapidly activated inward component of the delayed rectifier potassium current IKr).12, 13, 14, 15 In addition, sotalol does not appear to block sodium channels at usual doses (although it may at relatively high doses),12, 16, 26, 27 and pharmacologic differences of the drug at potassium and sodium channels compared with class I antiarrhythmic agents (e.g., mexiletine, procainamide, propafenone, quinidine) have been proposed as possibly contributing to potential clinical superiority of sotalol in the management of ventricular tachyarrhythmias.12 However, other factors also may be involved.12
Commercially available sotalol is a racemic mixture of the 2 optical isomers.1, 7, 11, 404 Both isomers exhibit class III antiarrhythmic activity,1, 7, 11, 14, 15 but only the l -isomer exhibits β-blocking activity.1, 7, 11, 14, 404
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 25 mg/5 mL | ||
Tablets | 80 mg* | Betapace® (scored) | ||
Betapace AF® (scored) | Covis | |||
Sorine® (scored) | ||||
Sotalol Hydrochloride Tablets (scored) | ||||
120 mg* | Betapace® (scored) | Covis | ||
Betapace AF® (scored) | Covis | |||
Sorine® (scored) | Upsher-Smith | |||
Sotalol Hydrochloride Tablets (scored) | ||||
160 mg* | Betapace® (scored) | Covis | ||
Betapace AF® (scored) | Covis | |||
Sorine® (scored) | Upsher-Smith | |||
Sotalol Hydrochloride Tablets (scored) | ||||
240 mg* | Sorine® (scored) | Upsher-Smith | ||
Sotalol Hydrochloride Tablets (scored) | ||||
Parenteral | Injection concentrate, for IV infusion | 15 mg/mL* | Sotalol Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Covis Pharma. Betapace® and Betapace AF® (sotalol hydrochloride) tablets prescribing information. Zug, Switzerland; 2016 May.
2. Bigger JT, Hoffman BF. Antiarrhythmic drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:867.
3. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol . 1990; 65:74-81A.
4. Kehoe RF, Zheutlin TA, Dunnington CS et al. Safety and efficacy of sotalol in patients with drug-refractory sustained ventricular tachyarrhythmias. Am J Cardiol . 1990; 65:58-64A.
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8. Berlex Laboratories. Betapace® (sotalol hydrochloride) product monograph. Wayne, NJ; 1992 Dec.
9. Food and Drug Administration Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD: 1996 Jul.
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16. Singh BN, Vaughan Williams EM. A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474. Br J Pharmacol . 1970; 39:675-87. [PubMed 5485144][PubMedCentral]
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18. Ruskin JN. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med . 1989; 321:386-8. [PubMed 2501683]
19. Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med . 1991; 324:781-8. [PubMed 1900101]
20. Food and Drug Administration. Enkaid and Tambocor use in non-life-threatening arrhythmias halted. FDA Talk Paper. 1989 Apr 25.
21. Department of Health and Human Services. Background statement regarding encainide, flecainide, and moricizine. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 1989 Apr.
22. The Cardiac Arrhythmia Suppression Trial II investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med . 1992; 327:227-33. [PubMed 1377359]
26. Berlex Laboratories, Wayne, NJ: Personal communication.
27. Carmeliet E. Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and purkinje fibers. J Pharmacol Exp Ther . 1985; 323: 817-25.
28. MacNeil DJ, Davies RO, Deitchman D. Clinical safety profile of sotalol in the treatment of arrhythmias. Am J Cardiol . 1993; 72:44-50A.
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32. Wagner X, Jouglard J, Moulin M et al. Coadministration of flecainide acetate and sotalol during pregnancy: lack of teratogenic effects, passage across the placenta, and excretion in human breast milk. Am Heart J . 1990; 119:700-2. [PubMed 1689933]
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