SOTYLIZE (Page 2 of 7)

3 DOSAGE FORMS AND STRENGTHS

Oral solution: 5 mg/mL, in 250 mL or 480 mL bottles.

4 CONTRAINDICATIONS

• Sinus bradycardia (<50 bpm during waking hours), sick sinus syndrome or second and third degree AV block unless a functioning pacemaker is present
• Congenital or acquired long QT syndromes, baseline QT interval >450 ms
• Cardiogenic shock, uncontrolled heart failure
• Creatinine clearance <40 mL/min
• Serum potassium <4 meq/L
• Bronchial asthma or related bronchospastic conditions
• Known hypersensitivity to sotalol

5 WARNINGS AND PRECAUTIONS

5.1 QT Prolongation and Proarrhythmia

Ventricular arrhythmias

SOTYLIZE can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to the concentration of sotalol. Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval [see Dosage and Administration (2)].

Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents

The use of SOTYLIZE in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include many 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. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.

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 ADVERSE REACTIONS

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.

Adults:

Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects. The common documented beta-blocking adverse reactions (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related.

Serious Adverse Reactions

SOTYLIZE can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to the plasma level of sotalol. Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of TdP [see Warnings and Precautions (5.1)].

Proarrhythmia in Atrial Fibrillation Patients. In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of TdP reported (0.6%) during the controlled phase of treatment with oral sotalol.

Prolongation of the QT interval is dose related, increasing from baseline an average of 25, 40, and 50 msec in the 80, 120, and 160 mg groups, respectively, in the oral dose-response study [see Clinical Trials (14.2)].

Proarrhythmia in Ventricular Arrhythmia Patients. In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT was about 0.7%. Additionally, in approximately 1% of patients, deaths were considered possibly drug related; such cases, although difficult to evaluate, may have been associated with proarrhythmic events. Torsade de Pointes arrhythmias in patients with VT/VF were dose related, as was the prolongation of QT (QTc) interval, as shown in Table 2 below.

Table 2: Percent Incidence of Torsade de Pointes and Mean QT_c Interval by Dose For Patients With Sustained VT/VF

Daily Dose (mg)	Incidence of Torsade de Pointes	Mean QTc * (msec)
( ) Number of patients assessed
* Highest on-therapy value
80	0 (69)	463 (17)
160	0.5 (832)	467 (181)
320	1.6 (835)	473 (344)
480	4.4 (459)	483 (234)
640	3.7 (324)	490 (185)
>640	5.8 (103)	512 (62)

Table 3 below relates the incidence of Torsade de Pointes to on-therapy QT_c and change in QT_c from baseline. It should be noted, however, that the highest on-therapy QT_c was in many cases the one obtained at the time of the Torsade de Pointes event, so that the table overstates the predictive value of a high QT_c .

Table 3: Relationship Between QT_c Interval Prolongation and Torsade de Pointes

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

In addition to dose and presence of sustained VT, other risk factors for Torsade de Pointes were gender (females had a higher incidence), excessive prolongation of the QT_c interval and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appear to have the highest risk for serious proarrhythmia (7%). Of the ventricular arrhythmia patients experiencing Torsade de Pointes, approximately two-thirds spontaneously reverted to their baseline rhythm. The others were either converted electrically (D/C cardioversion or overdrive pacing) or treated with other drugs [see Overdosage (10)]. It is not possible to determine whether some sudden deaths represented episodes of Torsade de Pointes, but in some instances sudden death did follow a documented episode of Torsade de Pointes. Although sotalol therapy was discontinued in most patients experiencing Torsade de Pointes, 17% were continued on a lower dose.

Other Adverse Reactions

In a pooled clinical trial population consisting of four placebo-controlled studies with 275 patients with AFIB/AFL treated with 160-320 mg of oral sotalol, the following adverse events were reported at least 2% more frequently in the 160-240 mg sotalol treated patients than in placebo patients (see Table 4). The data are presented by incidence of events in the oral sotalol and placebo groups by body system and daily dose.

Table 4: Incidence (%) of Common Adverse Reactions (≥2% more frequent in patients treated in the 160-240 mg group than on placebo) in Four Placebo-Controlled Studies of Patients with AFIB/AFL Treated with Oral Sotalol

	Placebo	Oral SotalolTotal Daily Dose
Body System/Adverse Reactions (Preferred Term)	N=282	160-240N=153	>240-320N=122
CARDIOVASCULAR
Bradycardia	2.5	13.1	12.3
Abnormality ECG	0.4	3.3	2.5
GASTROINTESTINAL
Nausea/Vomiting	5.3	7.8	5.7
Diarrhea	2.1	5.2	5.7
GENERAL
Fatigue	8.5	19.6	18.9
Hyperhidrosis	3.2	5.2	4.9
Weakness	3.2	5.2	4.9
NERVOUS SYSTEM
Dizziness	12.4	16.3	13.1

In AFIB/AFL patients, discontinuation because of unacceptable adverse reactions was necessary in 17% of the patients, and occurred in 10% of patients less than two weeks after starting treatment. The most common adverse reactions leading to discontinuation of sotalol were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

In clinical trials involving 1292 patients with sustained VT/VF, the common adverse events were similar to those described for the AFIB/AFL population.

One case of peripheral neuropathy which resolved on discontinuation of sotalol and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study. Elevated blood glucose levels and increased insulin requirements can occur in diabetic patients.

Pediatric Patients:

In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m² with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed. One (1) patient, receiving 30 mg/m² daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular adverse events were seen at the 90 and 210 mg/m² daily dose levels. They included QT prolongations (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient). Values for QT_c ≥525 msec were seen in 2 patients at the 210 mg/m² daily dose level. Serious adverse events including death, Torsade de Pointes, other proarrhythmias, high-degree A-V blocks and bradycardia have been reported in infants and/or children.