1.1 Documented Life-Threatening Ventricular Arrhythmia

SOTYLIZE (sotalol hydrochloride) is indicated for the treatment of ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening.

Upon initiation of SOTYLIZE, increasing doses, and prior to chronic outpatient use, evaluated response by a suitable method (e.g., PES or Holter monitoring) at steady-state blood levels of drug.

1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter

SOTYLIZE is indicated 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.

2.1 General Rules and Safety Measures of Oral Sotalol Therapy

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol should be hospitalized for at least 3 days or until steady-state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate oral sotalol therapy in the presence of personnel trained in the management of serious ventricular arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy with sotalol. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval for sotalol.

Start sotalol therapy only if the baseline QTc interval is <450 msec. During initiation and titration, monitor the QT interval after each dose. If the QTc interval prolongs to 500 msec or greater, reduce the dose, increase the interval between doses, or discontinue the drug.

Administer sotalol twice daily in patients with a creatinine clearance >60 mL/min or once daily in patients with creatinine clearance between 40 and 60 mL/min. Sotalol is not recommended in patients with a creatinine clearance <40 mL/min. The recommended initial oral dose of sotalol is 80 mg (once or twice daily) and is initiated and titrated as described below.

Patients to be discharged on SOTYLIZE therapy from an in-patient setting should have an adequate supply of SOTYLIZE, to allow uninterrupted therapy until the patient can fill a SOTYLIZE prescription.

Advise patients who miss a dose to take just the next dose at the usual time.

For patients discharged and taking compounded sotalol oral solution filled by the pharmacy, consider switching to SOTYLIZE while in an out-patient setting.

Table 1 shows the appropriate volume of SOTYLIZE solution for typical doses.

2.2 Ventricular Arrhythmia

The recommended initial dose of oral sotalol for the treatment of ventricular arrhythmia is 80 mg, once or twice daily based on creatinine clearance [see Dosage and Administration (2.1)]. The dose may be increased in increments of 80 mg per day every 3 days as needed, provided QTc < 500 msec. The usual therapeutic effect is observed with oral doses of 80 to 160 mg once or twice a day. Oral doses as high as 240-320 mg once or twice a day have been utilized in patients with refractory life-threatening arrhythmias.

Pediatrics

As in adults, initiate in the hospital after appropriate clinical assessment, gradually increase dose as required, and monitor QTc and heart rate.

For children aged 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing.

For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Allow at least 36 hours between dose increments to attain steady-state plasma concentrations of sotalol in patients with normal renal function.

For children aged 2 years or younger, reduce the dose as shown in Figure 1.

Figure 1: Factor For Dose Adjustment by Age

For a child with normal renal function aged 1 month, the initial starting dose would be (30 × 0.7) = 21 mg/m2, administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 × 0.3) = 9 mg/m2. Use similar calculations for dose titration.

Since the half-life of sotalol increases below about 2 years, time to steady-state will also increase. Thus, in neonates the time to steady-state may be a week or longer.

2.3 Symptomatic AFIB/AFL

The recommended initial dose of oral sotalol for the treatment of symptomatic AFIB/AFL is 80 mg, once or twice daily based on creatinine clearance [see Dosage and Administration (2.1)]. If that dose level at steady-state does not acceptably reduce the time to recurrence of arrhythmia and is tolerated with QTc <520 msec, increase the dose to 160 mg orally once or twice a day every three days. In the U.S. multicenter dose-response study, 120 mg orally once or twice a day was found to be the most effective dose in prolonging the time to ECG-documented symptomatic recurrence of AFIB/AFL.

2.4 Considerations in Renal Impairment

Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QTc is most important and it will take much longer to reach steady-state with any dose and/or frequency of administration.

5.1 QT Prolongation and Proarrhythmia

5.2 Bradycardia/Heart Block

In studies of oral sotalol, the incidence of bradycardia (as determined by the investigators) in the supraventricular arrhythmia population treated with oral sotalol was 13%, and led to discontinuation in 2.4% of patients. Bradycardia itself increases the risk of Torsade de Pointes, so carefully monitor patients receiving concomitant digoxin.

5.3 Sick Sinus Syndrome

In general, SOTYLIZE is not recommended in patients with sick sinus syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus pauses or sinus arrest. In patients with AFIB and sinus node dysfunction, sotalol increases the risk of Torsade de Pointes, especially after cardioversion. Sotalol augments bradycardia following cardioversion. Patients with AFIB/AFL associated with the sick sinus syndrome may be treated with sotalol if they have an implanted pacemaker for control of bradycardia symptoms.

5.4 Hypotension

Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension, including decompensated heart failure. Monitor hemodynamics in patients with marginal cardiac compensation.

5.5 Recent Acute MI

Oral sotalol has been used in a controlled trial following an acute myocardial infarction without evidence of increased mortality [see Clinical Studies (14.3)]. Although specific studies of its use in treating atrial arrhythmias after infarction have not been conducted, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia or prolonged QT interval apply. Experience in the use of sotalol to treat ventricular arrhythmias in the early phase of recovery from acute MI is limited. In the first 2 weeks post-MI, careful dose titration is especially important, particularly in patients with markedly impaired ventricular function.

5.6 Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias and, in some cases, myocardial infarction have been reported after abrupt discontinuation of beta-blocker therapy. Therefore, when discontinuing chronically administered sotalol, particularly in patients with ischemic heart disease, carefully monitor the patient and consider the temporary use of an alternate beta-blocker if appropriate. If possible, the dosage of sotalol should be gradually reduced over a period of one to two weeks. If angina or acute coronary insufficiency develops, appropriate therapy should be instituted promptly. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized in patients receiving sotalol, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.

5.7 Electrolyte Disturbances

SOTYLIZE should not be used in patients with hypokalemia or hypomagnesemia prior to correction of imbalance, as these conditions increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs.

5.8 Renal Impairment

Sotalol 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 [see Dosage and Administration (2)].

5.9 Non-Allergic Bronchospasm

Patients with bronchospastic diseases should in general not receive beta-blockers. If SOTYLIZE is to be administered, use the smallest effective dose, to minimize inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors.

5.10 Diabetes

Beta-blockade may mask some important premonitory signs of acute hypoglycemia (e.g., tachycardia) in patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia.

5.11 Thyrotoxicosis

Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal of SOTYLIZE which might exacerbate symptoms of hyperthyroidism, including thyroid storm.

5.12 Anaphylaxis

While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

5.13 Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sotalol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Postmarketing experience with sotalol shows an adverse event profile similar to that described above from clinical trials. Voluntary reports since introduction include rare reports (less than one report per 10,000 patients) of: emotional liability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.

7.1 Digoxin

Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of heart failure, a known risk factor for proarrhythmia, in the patients receiving digoxin.

7.2 Calcium-Blocking Drugs

Sotalol and calcium blocking drugs can be expected to have additive effects on atrioventricular conduction, ventricular function, and blood pressure.

7.3 Catecholamine-Depleting Agents

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for hypotension and marked bradycardia which may produce syncope.

7.4 Insulin and Oral Antidiabetic Agents

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked.

7.5 Beta-2-Receptor Stimulants

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

7.6 Clonidine

Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine.

7.7 Drugs that Prolong QT Interval and Antiarrhythmic Agents

Sotalol has not been studied with other drugs that prolong the QT interval such as antiarrhythmics, some phenothiazines, tricyclic antidepressants, certain oral macrolides and certain quinolone antibiotics. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with sotalol. In clinical trials, sotalol was not administered to patients previously treated with oral amiodarone for >1 month in the previous three months. Class Ia antiarrhythmic drugs such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with sotalol because of their potential to prolong refractoriness [see Warnings and Precautions (5.1)]. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.

7.8 Antacids

Administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it may result in a reduction in Cmax and AUC of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

8.1 Pregnancy

8.3 Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Discontinue nursing or SOTYLIZE.

8.4 Pediatric Use

The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Dosage and Administration (2.2) and Clinical Pharmacology (12)].

8.5 Geriatric Use

Impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation [see Clinical Pharmacology (12.3)].

8.6 Patients with Renal Impairment

Sotalol 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 [see Dosage and Administration (2)]. The dosing interval (time between divided doses) of sotalol should be modified when creatinine clearance is lower than 60 mL/min [see Dosage and Administration (2.4)]. Sotalol is contraindicated when creatinine clearance is less than 40 mL/min [see Contraindications (4)].

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 (2-16 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 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, magnesium sulfate, potassium replacement. Once Torsade de Pointes is terminated, transvenous cardiac pacing or an isoproterenol infusion to increase heart rate can be employed.

12.1 Mechanism of Action

Sotalol 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 two isomers, both of which 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 an oral dose of 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

In healthy subjects, the oral bioavailability of sotalol is 90-100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2-3 days (i.e., after 5-6 doses when administered twice daily). Over the oral dosage range 160-640 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 (2.1)]. 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 every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on average between 2-3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1-2 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 <0.33m2) 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%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137-275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m2) or in mice, during a 24-month study at 4141-7122 mg/kg/day (approximately 450-750 times the MRHD as mg/kg or 36-63 times the MRHD as mg/m2).

Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.

No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/m2) prior to mating, except for a small reduction in the number of offspring per litter.

Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m2), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m2) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m2) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m2), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response.

14.1 Clinical Studies in Ventricular Arrhythmias

Oral sotalol has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), sotalol was significantly superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the response was dose-related through 640 mg/day with 80-85% of patients having at least a 75% reduction of VPCs. Sotalol was also superior, at the doses evaluated, to propranolol (40-80 mg TID) and similar to quinidine (200-400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of sotalol and procainamide given intravenously (total of 2 mg/kg sotalol vs. 19 mg/kg of procainamide over 90 minutes), sotalol suppressed PES induction in 30% of patients vs. 20% for procainamide (p=0.2).

In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol hydrochloride was compared with 6 other drugs (procainamide, quinidine, mexiletine, propafenone, and imipramine). Overall response, limited to first randomized drug, was 39% for sotalol and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), sotalol yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), sotalol, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75-80%). The most commonly used doses of sotalol hydrochloride in this trial were 320-480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more. It cannot be determined, however, in the absence of a controlled comparison of sotalol vs. no pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

14.2 Clinical Studies in Supraventricular Arrhythmias

Sotalol 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 (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40-60 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 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 2, Table 5 and Table 6.

Figure 2: Study 1 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

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, oral sotalol 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 (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%).

Tables 7 and 8 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 3: Study 2 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since Randomization

14.3 Clinical Studies in Patients with Myocardial Infarction

In a multicenter, double-blind, randomized study, 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 5-14 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. There was, however, a suggestion of an early (i.e., first 10 days) excess mortality (3% on sotalol vs. 2% on placebo).

In a second small trial (n=17 randomized to sotalol) where sotalol was administered at high doses (e.g., 320 mg twice daily) to high-risk postinfarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol.

Store at 20°C to 25°C (68°F -77°F); excursions permitted between 15°C and 30°C (59°F-86°F) [see USP Controlled Room Temperature].

QT Prolongation and Proarrhythmia

Advise patients to contact their healthcare provider in the event of syncope, pre-syncopal symptoms and cardiac palpitations such as fainting, dizziness or fast heartbeats. Advise patients that their healthcare provider will monitor their electrolytes and ECG during treatment [see Warnings and Precautions (5.1)].

Diarrhea, Unusual Sweating, Vomiting, Reduced Appetite, Excessive Thirst

Advise patients to contact their healthcare provider in the event of conditions conducive to electrolyte changes such as severe diarrhea, unusual sweating, vomiting, less appetite than normal or excessive thirst [see Warnings and Precautions (5.7)].

Administration

Advise patients to not change the SOTYLIZE dose prescribed by their healthcare provider.

Advise patients that, to be sure doses are accurately measured, doses for children and infants should be measured using an appropriate measuring device such as an oral syringe. Advise them that a teaspoon or tablespoon should not be used to measure SOTYLIZE doses since doing so might lead to confusion and the wrong dose.

Advise patients that they should not miss a dose, but if they do miss a dose they should not double the next dose to compensate for the missed dose; they should take the next dose at the regularly scheduled time [see Dosage and Administration (2)].

Advise patients to not interrupt or discontinue SOTYLIZE without their physician's advice, that they should get their prescription for sotalol filled and refilled on time so they do not interrupt treatment [see Dosage and Administration (2.1)].

Advise patients that they should not take SOTYLIZE if they also take another medicine that contains sotalol.

Advise patients that if overdose occurs or they take too much SOTYLIZE, take their SOTYLIZE medicine bottle with them and go to the nearest emergency room immediately. Overdoses can potentially cause life-threatening abnormal heart beats and possibly death.

Advise patients to contact their healthcare provider if they develop bradycardia.

Drug Interactions

Advise patients not to start taking other medications without first discussing new medications with their healthcare provider.

Antacids

Advise patients that they should avoid taking SOTYLIZE within 2 hours of taking antacids that contain aluminum oxide or magnesium hydroxide [see Drug Interactions (7.8)].