Sotalol

Sotalol is the generic form of the brand-name drug Betapace, used to treat a serious irregular heartbeat (arrhythmia).

The prescription medicine is in a class of drugs known as anti-arrhythmics. It works by helping the heart muscle beat regularly for a longer amount of time.

The Food and Drug Administration (FDA) originally approved a formulation of sotalol in 1992.

The medicine is manufactured as Betapace by Bayer HealthCare Pharmaceuticals.

Sotalol Warnings

Sotalol contains a black-box warning because it could cause a new or worsened irregular heartbeat that may be life-threatening.

For the first three days of treatment, you'll receive your sotalol doses in a medical facility where your heart rhythm can be monitored.

Sotalol is manufactured under two different brand names, Betapace and Betapace AF. These medicines are used for different types of irregular heartbeats and shouldn't be taken interchangeably.

Don't change your brand of sotalol without first talking to your physician.

Before taking this medicine, tell your doctor if you have or have ever had:

• Kidney disease
• Prolonged QT interval or long QT syndrome (heart rhythm disorders)
• Heart disease or heart failure
• Liver disease
• Asthma or other lung disease
• Severe allergies or allergies to medicines
• Diabetes
• Low blood potassium or magnesium levels
• An overactive thyroid
• A tumor on your adrenal gland
• Low blood pressure
• Blood vessel disease

Sotalol controls your irregular heartbeat, but it won't cure your condition. Continue to take this drug even if you feel well.

Don't stop taking sotalol without first talking to your physician. Stopping the medicine abruptly may cause chest pain or a heart attack.

If you have diabetes, sotalol may affect your blood sugar levels. Check your levels often, and talk to your doctor before changing any doses of your diabetes medicines.

Tell your healthcare provider you're taking sotalol before having any type of surgery, including a dental procedure.

Keep all appointments with your doctor and laboratory while taking sotalol. Your doctor will probably want to check your blood pressure and pulse rate often.

Pregnancy and Sotalol

This drug isn't likely to harm an unborn baby.

However, talk to your doctor if you're pregnant or might become pregnant before taking sotalol.

Sotalol is found in breast milk. Don't breastfeed while taking this medicine.

Betapace/Betapace AF contains sotalol hydrochloride, an antiarrhythmic drug with Class II (betaadrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. Betapace is supplied as a light-blue, capsule-shaped tablet for oral administration. Betapace AF is supplied as a white, capsule-shaped tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3 S•HCl and is represented by the following structural formula:

Betapace

Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose, starch, stearic acid, magnesium stearate, colloidal silicon dioxide, and FD&C blue color #2 (aluminum lake, conc.).

Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose, starch, stearic acid, magnesium stearate, and colloidal silicon dioxide.

Avoid taking an antacid within 2 hours before or 2 hours after you take sotalol. Some antacids can make it harder for your body to absorb sotalol.

Usual Adult Dose for Atrial Fibrillation:

Note: The generic form of this drug is used for atrial fibrillation or ventricular arrhythmia. The trade name Betapace (R) is for ventricular arrhythmia only and the trade name Betapace AF (R) is for atrial fibrillation only. These two trade names are not interchangeable.

SOTALOL: (ATRIAL FIBRILLATION, VENTRICULAR ARRHYTHMIA):
-Initial dose: 80 mg orally 2 times a day
-Doses should be adjusted gradually every 3 days in order to attain steady state plasma concentrations and allow for monitoring of QT intervals.
-Maintenance dose: The initial dose may be increased, if needed, to 240 or 320 mg orally per day (120 to 160 mg orally 2 times a day).
-Some patients with life-threatening refractory ventricular arrhythmias may require 480 to 640 mg per day in divided doses.
Comment:
-Because of the long terminal elimination half-life of this drug, dosing on more than a twice a day regimen is usually not necessary.

ORAL [BETAPACE AF (R)}: (ATRIAL FIBRILLATION):
-(STEP 1) Electrocardiographic assessment: Prior to administration of the first dose, the CrCl and the QT interval should be determined. If the baseline QT is greater than 450 msec, Betapace AF (R) is contraindicated:
-(STEP 2): Calculate the CrCl for the patient.
-(STEP 3):
Initial dose:
-If the CrCl is less than 40 mL/day: Betapace AF (R) is contraindicated
-If the CrCl is 40 to 60 mL/min: 80 mg once a day
-If the CrCl is greater than 60 mL/min: 80 mg orally 2 times a day
-(STEP 4): Continuous ECG monitoring with QT interval measurements should begin after the first dose and every 2 to 4 hours after each additional dose.
-(STEP 5); If the 80 mg dose level is tolerated and the QT interval remains less than 500 msec after at least 3 days (after 5 or 6 doses if patient receiving once-daily dosing), the patient can be discharged. Alternatively, during hospitalization, the dose can be increased to 120 mg twice daily and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receiving once-daily dosing).
-If the 80 mg dose level (given twice a day or once-daily depending upon CrCl) does not reduce the frequency of relapses of atrial fibrillation/atrial flutter and is tolerated without excessive QT interval prolongation (i.e., greater than or equal to 520 msec), the dose level may be increased to 120 mg (twice a day or once-daily depending upon CrCl).
-If the 120 mg dose does not reduce the frequency of early relapse of atrial fibrillation/atrial flutter and is tolerated without excessive QT interval prolongation (greater than or equal to 520 msec), an increase to 160 mg (2 times a day or daily) depending upon CrCl), can be considered.
-Any increases in dosage should be done in a step-wise fashion as outlined above.
-Maintenance dose: 120 to 160 mg orally 2 times a day. Renal function and QT should be reevaluated regularly if medically warranted. If QT is 520 msec or greater (JT 430 msec or greater if QRS is greater than 100 msec), the dose should be reduced and patients should be carefully monitored until QT returns to less than 520 msec. If the QT interval is greater than or equal to 520 msec while on the lowest maintenance dose level (80 mg) the drug should be discontinued.

PARENTERAL:
-Initial: 112.5 mg IV once or twice daily
-Maintenance: 112.5 to 150 mg IV once or twice daily
-If 112.5 mg IV once or twice daily, at steady state, does not reduce the frequency of early relapse of arrhythmia and is tolerated without excessive QTc prolongation (greater than 520 msec), increase the dose to 150 mg IV once or twice daily.
-Start IV therapy only if the baseline QT interval is less than 450 msec. During initiation and titration, monitor the QT interval after the completion of each infusion. If the QT interval prolongs to 500 msec or greater, reduce the dose, decrease the infusion rate, or discontinue the drug.

Use: For the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.

Usual Adult Dose for Atrial Flutter:

Note: The generic form of this drug is used for atrial fibrillation or ventricular arrhythmia. The trade name Betapace (R) is for ventricular arrhythmia only and the trade name Betapace AF (R) is for atrial fibrillation only. These two trade names are not interchangeable.

SOTALOL: (ATRIAL FIBRILLATION, VENTRICULAR ARRHYTHMIA):
-Initial dose: 80 mg orally 2 times a day
-Doses should be adjusted gradually every 3 days in order to attain steady state plasma concentrations and allow for monitoring of QT intervals.
-Maintenance dose: The initial dose may be increased, if needed, to 240 or 320 mg orally per day (120 to 160 mg orally 2 times a day).
-Some patients with life-threatening refractory ventricular arrhythmias may require 480 to 640 mg per day in divided doses.
Comment:
-Because of the long terminal elimination half-life of this drug, dosing on more than a twice a day regimen is usually not necessary.

ORAL [BETAPACE AF (R)}: (ATRIAL FIBRILLATION):
-(STEP 1) Electrocardiographic assessment: Prior to administration of the first dose, the CrCl and the QT interval should be determined. If the baseline QT is greater than 450 msec, Betapace AF (R) is contraindicated:
-(STEP 2): Calculate the CrCl for the patient.
-(STEP 3):
Initial dose:
-If the CrCl is less than 40 mL/day: Betapace AF (R) is contraindicated
-If the CrCl is 40 to 60 mL/min: 80 mg once a day
-If the CrCl is greater than 60 mL/min: 80 mg orally 2 times a day
-(STEP 4): Continuous ECG monitoring with QT interval measurements should begin after the first dose and every 2 to 4 hours after each additional dose.
-(STEP 5); If the 80 mg dose level is tolerated and the QT interval remains less than 500 msec after at least 3 days (after 5 or 6 doses if patient receiving once-daily dosing), the patient can be discharged. Alternatively, during hospitalization, the dose can be increased to 120 mg twice daily and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receiving once-daily dosing).
-If the 80 mg dose level (given twice a day or once-daily depending upon CrCl) does not reduce the frequency of relapses of atrial fibrillation/atrial flutter and is tolerated without excessive QT interval prolongation (i.e., greater than or equal to 520 msec), the dose level may be increased to 120 mg (twice a day or once-daily depending upon CrCl).
-If the 120 mg dose does not reduce the frequency of early relapse of atrial fibrillation/atrial flutter and is tolerated without excessive QT interval prolongation (greater than or equal to 520 msec), an increase to 160 mg (2 times a day or daily) depending upon CrCl), can be considered.
-Any increases in dosage should be done in a step-wise fashion as outlined above.
-Maintenance dose: 120 to 160 mg orally 2 times a day. Renal function and QT should be reevaluated regularly if medically warranted. If QT is 520 msec or greater (JT 430 msec or greater if QRS is greater than 100 msec), the dose should be reduced and patients should be carefully monitored until QT returns to less than 520 msec. If the QT interval is greater than or equal to 520 msec while on the lowest maintenance dose level (80 mg) the drug should be discontinued.

PARENTERAL:
-Initial: 112.5 mg IV once or twice daily
-Maintenance: 112.5 to 150 mg IV once or twice daily
-If 112.5 mg IV once or twice daily, at steady state, does not reduce the frequency of early relapse of arrhythmia and is tolerated without excessive QTc prolongation (greater than 520 msec), increase the dose to 150 mg IV once or twice daily.
-Start IV therapy only if the baseline QT interval is less than 450 msec. During initiation and titration, monitor the QT interval after the completion of each infusion. If the QT interval prolongs to 500 msec or greater, reduce the dose, decrease the infusion rate, or discontinue the drug.

Use: For the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.

Usual Adult Dose for Ventricular Arrhythmia:

Usual Adult Dose: Ventricular Arrhythmia:
(CA, US):
Note: The generic form of this drug is used for atrial fibrillation or ventricular arrhythmia. The trade name Betapace (R) is for ventricular arrhythmia only and the trade name Betapace AF (R) is for atrial fibrillation only. These two trade names are not interchangeable.

SOTALOL: (ATRIAL FIBRILLATION, VENTRICULAR ARRHYTHMIA):
-Initial dose: 80 mg orally 2 times a day
-Doses should be adjusted gradually every 3 days in order to attain steady state plasma concentrations and allow for monitoring of QT intervals.
-Maintenance dose: The initial dose may be increased, if needed, to 240 or 320 mg orally per day (120 to 160 mg orally 2 times a day).
-Some patients with life-threatening refractory ventricular arrhythmias may require 480 to 640 mg per day in divided doses.

Comment:
-Because of the long terminal elimination half-life of this drug, dosing on more than a twice a day regimen is usually not necessary.

ORAL (BETAPACE): (VENTRICULAR ARRHYTHMIA):
-Initial: 80 mg twice daily
-The initial dose may be increased 120 to 160 mg twice daily. The dosage should be adjusted gradually allowing 3 days between dosing increments in order to attain steady-state plasma concentrations and to allow monitoring of QT intervals. Graded dose adjustment will help prevent doses that are higher than necessary to control the arrhythmia. Most patients obtain a therapeutic response with a total daily dose of 160 to 320 mg given in two or three divided doses.

PARENTERAL:
-Initial: 75 mg IV infused over 5 hours once or twice daily based on the creatinine clearance.
-Maintenance: 75 to 300 mg infused over 5 hours once or twice daily based on the creatinine clearance.
-The dose may be increased in increments of 75 mg/day every 3 days. Doses as high as 225 or 300 mg IV have been utilized in patients with refractory life-threatening arrhythmias.
-Start IV therapy only if the baseline QT interval is less than 450 msec. During initiation and titration, monitor the QT interval after the completion of each infusion. If the QT interval prolongs to 500 msec or greater, reduce the dose, decrease the infusion rate, or discontinue the drug.

Use: Documented life-threatening ventricular arrhythmia

Many drugs can interact with sotalol. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with sotalol, especially:

• digoxin;

• insulin or oral diabetes medicine;

• blood pressure medication; or

• any other medicine that contains sotalol.

This list is not complete and many other drugs can interact with sotalol. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Mechanism of Action

Sotalol hydrochloride has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol hydrochloride is a racemic mixture of d- and l-Sotalol. Both isomers have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of Sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiological effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of Sotalol is observed at daily doses ≥90 mg/m2 in children.

Electrophysiology

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of Sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 to 100 msec in QT and 10 to 40 msec in QTc. In a study of patients with atrial fibrillation (AFIB)/flutter (AFIB/AFL) receiving three different oral doses of Sotalol hydrochloride (AF) given q12h (or q24h in patients with a reduced creatinine clearance), mean increases in QT intervals measured from 12-lead ECGs of 25 msec, 40 msec and 54 msec were found in the 80 mg, 120 mg, and 160 mg dose groups, respectively. (See WARNINGS for description of relationship between QTc and Torsade de Pointes type arrhythmias.) No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with Sotalol, the average defibrillatory threshold was 6 joules (range 2 to 15 joules) compared to a mean of 16 joules for a non-randomized comparative group primarily receiving amiodarone.

In a dose-response trial comparing three dose levels of Sotalol hydrochloride (AF), 80 mg, 120 mg, and 160 mg with placebo given q12h (or q24h in patients with a reduced renal creatinine clearance) for the prevention of recurrence of symptomatic atrial fibrillation (AFIB)/flutter (AFL), the mean ventricular rate during recurrence of AFIB/AFL was 125, 107, 110 and 99 beats/min in the placebo, 80 mg, 120 mg and 160 mg dose groups, respectively (p <0.017 for each Sotalol dose group versus placebo). In another placebo controlled trial in which Sotalol hydrochloride (AF) was titrated to a dose between 160 and 320 mg/day in patients with chronic AFIB, the mean ventricular rate during recurrence of AFIB was 107 and 84 beats/min in the placebo and Sotalol hydrochloride (AF) groups, respectively (p <0.001).

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QTc interval, in msec (%), were 2(+1%), 14(+4%) and 29(+7%) msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval, in msec (%), were 23(+6%), 36(+9%) and 55(+14%) msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33 m2) showed a tendency for larger Class III effects (ΔQTc) and an increased frequency of prolongations of the QTc interval as compared with the larger children (BSA≥0.33 m2). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33 m2). Both the Class III and beta-blocking effects of Sotalol were linearly related with the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of Sotalol produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed non-significant increases of 25% and 8%, respectively. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. One patient was discontinued because of worsening congestive heart failure. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by Sotalol, and total peripheral resistance increases by a small amount.

In hypertensive patients, Sotalol produces significant reductions in both systolic and diastolic blood pressures. Although Sotalol is usually well-tolerated hemodynamically, caution should be exercised in patients with marginal cardiac compensation as deterioration in cardiac performance may occur. (See WARNINGS, Congestive Heart Failure.)

Clinical Studies

Sotalol hydrochloride (AF) has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of Sotalol hydrochloride (AF) (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40 to 60 mL/min) the same doses were given once daily. Patients were not randomized for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 meq/L) or hypomagnesemia (serum magnesium <1.5 meq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to ≥520 msec (or JT ≥430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol hydrochloride (AF) was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 1 and Tables 1 and 2.

Figure 1
Study 1 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

Table 1
Study 1 - Patient Status at 12 Months

a Symptomatic AFIB/AFL

b Efficacy endpoint of Study 1: study treatment stopped

Please note that columns do not add up to 100% due to discontinuations (D/C) for "other" reasons.

Table 2
Study 1 - Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, Sotalol hydrochloride (AF) was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, ≥3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment. After successful cardioversion patients were randomized to receive placebo (n=114) or Sotalol hydrochloride (AF) (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Figure 2 and Tables 3 and 4 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

Figure 2:
Study 2 – Time to First ECG – Documented recurrence of Symptomatic AFIB/AFL/Death since Randomization

Table 3:
Study 2 - Patient Status at 6 Months

a Symptomatic or asymptomatic AFIB/AFL

b Efficacy endpoint of Study 2; study treatment stopped

Table 4
Study 2 - Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months

In a multicenter double-blind randomized study reported by D. Julian et al, the effect of Sotalol 320 mg once daily was compared with that of placebo in 1456 patients (randomized 3:2, Sotalol to placebo) surviving an acute myocardial infarction (MI). Treatment was started 5 to 14 days after infarction. Patients were followed for 12 months. The mortality rate was 7.3% in the Sotalol group and 8.9% in the placebo group, not a statistically significant difference. Although the results do not show evidence of a benefit of Sotalol in this population, they do not show an added risk in post MI patients receiving Sotalol.

Pharmacokinetics

In healthy subjects, the oral bioavailability of Sotalol is 90 to 100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 to 3 days (i.e., after 5 to 6 doses when administered twice daily). Over the dosage range 160 to 640 mg/day Sotalol displays dose proportionality with respect to plasma concentrations. Distribution occurs to a central (plasma) and to a peripheral compartment, with a mean elimination half-life of 12 hours. Dosing every 12 hours results in trough plasma concentrations, which are approximately one-half of those at peak.

Sotalol does not bind to plasma proteins and is not metabolized. Sotalol shows very little intersubject variability in plasma levels. The pharmacokinetics of the d and l enantiomers of Sotalol are essentially identical. Sotalol crosses the blood brain barrier poorly. Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment (see DOSAGE AND ADMINISTRATION). Age per se does not significantly alter the pharmacokinetics of Sotalol, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation. The absorption of Sotalol was reduced by approximately 20% compared to fasting when it was administered with a standard meal. Since Sotalol is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of Sotalol.

The combined analysis of two unblinded, multicenter trials (a single dose and a multiple dose study) with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of Sotalol to be first order. A daily dose of 30 mg/m2 of Sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 were administered q8h in the multi-dose study. After rapid absorption with peak levels occurring on average between 2 to 3 hours following administration, Sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 to 2 days. The average peak to trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for the pharmacokinetics of Sotalol. The smallest children (BSA<0.33 m2) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%.

Renal Impairment

Sotalol hydrochloride (AF) is eliminated principally via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of Sotalol hydrochloride (AF). Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION.

Information for Patients

Please refer to the patient package insert.

Prior to initiation of Sotalol (AF) therapy, the patient should be advised to read the patient package insert and reread it each time therapy is renewed. The patient should be fully instructed on the need for compliance with the recommended dosing of Sotalol (AF), the potential interactions with drugs that prolong the QT interval and other antiarrhythmics, and the need for periodic monitoring of QT and renal function to minimize the risk of serious abnormal rhythms.

Assessment of patients' medication history should include all over-counter, prescription and herbal/natural preparations with emphasis on preparations that may affect the pharmacodynamics of Sotalol (AF) such as other cardiac antiarrhythmic drugs, some phenothiazines, bepridil, tricyclic antidepressants and oral macrolides (see WARNINGS, Use With Drugs That Prolong QT Interval and Antiarrhythmic Agents). Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing Sotalol (AF) therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter medicine.

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.

Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Intentional or accidental overdosage with Sotalol has rarely resulted in death.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of Sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with Sotalol (AF) should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing Sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant.

Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

APOTEX CORP. NDC 60505-0223-1

Sotalol HYDROCHLORIDE TABLETS, USP (AF)

120 mg

Rx only

100 Tablets

• Sotalol HCl
• Sotalol Hydrochloride

Terminal half-life increases with renal impairment.

Atrial fibrillation in patients with hypertrophic cardiomyopathy (HCM) (alternative antiarrhythmic)

Based on the 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy, sotalol given as an alternative antiarrhythmic for atrial fibrillation in patients with hypertrophic cardiomyopathy (HCM) is effective and recommended in the management of this condition.

Monomorphic ventricular tachycardia (hemodynamically stable)

Data from one randomized double-blind study in a limited number of patients comparing the effectiveness of IV sotalol to IV lidocaine for the treatment of sustained hemodynamically stable ventricular tachycardia (VT) suggest that IV sotalol may be beneficial for the treatment of this condition [Ho 1994]. Additional data from an open-label electrophysiology study evaluating the effects of IV sotalol as a 1-minute or a 5-minute infusion on the right ventricular effective refractory period in patients with induced sustained VT safely demonstrated a rapid onset of the electrophysiological effects [Ho 1995]. Additional trials may be necessary to further define the role of IV sotalol in the treatment of this condition.

Based on the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, IV sotalol may be used to treat ongoing hemodynamically stable monomorphic VT.

Supraventricular tachycardia

Based on the American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines for the management of patients with supraventricular arrhythmias, sotalol may be a reasonable treatment for a variety of symptomatic supraventricular tachycardias (atrioventricular nodal reentrant tachycardia [AVNRT], atrioventricular reentrant tachycardia [AVRT], and focal atrial tachycardia [AT]) in patients who are not candidates for, or prefer not to undergo catheter ablation and in whom other therapies have failed or are contraindicated. Oral sotalol may be useful for the acute treatment or ongoing management of hemodynamically stable patients with adult congenital heart disease and recurrent atrial flutter or focal atrial tachycardia.

Additional Off-Label Uses

Fetal tachycardia

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect injection from freezing and light.

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification

Amifampridine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Antacids: May decrease the serum concentration of Sotalol. Management: Avoid simultaneous administration of sotalol and antacids. Administer antacids 2 hours after sotalol. Consider therapy modification

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May decrease the serum concentration of Beta-Blockers. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Bilastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Buprenorphine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Fingolimod: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Avoid combination

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Lidocaine (Topical): May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Antiarrhythmic Agents (Class III) may increase the serum concentration of Lidocaine (Topical). This mechanism specifically applies to amiodarone and dronedarone. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Mizolastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Propafenone: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Management: Concurrent use of propafenone with quinidine, amiodarone, or other class IA or class III antiarrhythmics should be avoided. Treatment with such agents should be withheld for at least 5 half-lives prior to initiation of propafenone. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy

Teneligliptin: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Commonly reported side effects of sotalol include: bradycardia, fatigue, and headache. Other side effects include: dyspnea, ecg abnormality, insomnia, and nausea and vomiting. See below for a comprehensive list of adverse effects.