WARNINGS
Ventricular Arrhythmia: BETAPACE AF (sotalol) 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 dose of BETAPACE AF. 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 BETAPACE AF dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
Treatment with BETAPACE AF must therefore be started only in patients observed for a minimum of three days on their maintenance dose in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance must precede administration of the first dose of BETAPACE AF. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.
Proarrhythmia in Atrial Fibrillation/Atrial Flutter Patients
In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of Torsade de Pointes reported (0.6%) during the controlled phase of treatment with BETAPACE AF. The incidence of Torsade de Pointes was significantly lower in those patients receiving total daily doses of 320 mg or less (0.3%), as summarized in Table 5 below. Both patients who had Torsade de Pointes in the group receiving >320 mg/day were receiving 640 mg/day. In the group receiving ≤320 mg daily, one case of TdP occurred at a daily dose of 320 mg on day 4 of treatment and one case occurred on a daily dose of 160 mg on day 1 of treatment.
Table 5 Incidence of Torsade de Pointes in Controlled Trials of AFIB and Other Supraventricular Arrhythmias | BETAPACE AF (Daily Dose) | |
|
Any
Dose
(N=659) |
>320
mg/day
(N=62) |
≤320
mg/day
(N=597) |
≤240
mg/day
(N=340) |
Placebo
(N=358) |
| n(%) | n(%) | n(%) | n(%) | n(%) |
| Torsade de Pointes | 4(0.6%) | 2(3.2%) | 2(0.3%) | 1(0.3%) | 0 |
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 clinical dose-response study. In this clinical trial BETAPACE AF treatment was not initiated if the QT interval was greater than 450 msec and during therapy the dose was reduced or discontinued if the QT interval was ≥520 msec.
Experience in patients with ventricular arrhythmias is also pertinent to the risk of Torsade de Pointes in patients with AFIB/AFL (see below).
Proarrhythmia in Ventricular Arrhythmia Patients: [see BETAPACE (sotalol hydrochloride) Package Insert]
In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during sotalol treatment was 4% and worsened VT in about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT in 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 6 below.
Table 6 Percent Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With Sustained VT/VF | Daily Dose (mg) | Incidence of Torsade de Pointes | Mean QTc
(msec) |
| 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 7 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline. It should be noted, however, that the highest on therapy QTc 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 QTc.
Table 7 Relationship Between QTc 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 |
| 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 QTc 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). 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.
Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents
The use of BETAPACE AF 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, bepridil, tricyclic antidepressants, and certain oral macrolides. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with BETAPACE AF. In clinical trials, BETAPACE AF 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 BETAPACE AF because of their potential to prolong refractoriness (see WARNINGS). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.
Congestive Heart Failure
Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have heart failure controlled by digitalis and/or diuretics, BETAPACE AF should be administered cautiously. Both digitalis and sotalol slow AV conduction. As with all beta-blockers, caution is advised when initiating therapy in patients with any evidence of left ventricular dysfunction. In a pooled data base of four placebo-controlled AFIB/AFL and PSVT studies, new or worsening CHF occurred during therapy with BETAPACE AF in 5 (1.2%) of 415 patients. In these studies patients with uncontrolled heart failure were excluded (i.e., NYHA Functional Classes III or IV). In other premarketing sotalol studies, new or worsened congestive heart failure (CHF) occurred in 3.3% (n=3257) of patients and led to discontinuation in approximately 1% of patients receiving sotalol. The incidence was higher in patients presenting with sustained ventricular tachycardia/fibrillation (4.6%, n=1363), or a prior history of heart failure (7.3%, n=696). Based on a life-table analysis, the one-year incidence of new or worsened CHF was 3% in patients without a prior history and 10% in patients with a prior history of CHF. NYHA Classification was also closely associated to the incidence of new or worsened heart failure while receiving sotalol (1.8% in 1395 Class I patients, 4.9% in 1254 Class II patients and 6.1% in 278 Class III or IV patients).
Electrolyte Disturbances
BETAPACE AF should not be used in patients with hypokalemia or hypomagnesemia prior to correction of imbalance, as these conditions can exaggerate the degree of QT prolongation, and 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.
Bradycardia/Heart Block
The incidence of bradycardia (as determined by the investigators) in the supraventricular arrhythmia population treated with BETAPACE AF® (N = 415) was 13%, and led to discontinuation in 2.4% of patients. Bradycardia itself increases the risk of Torsade de Pointes.
Recent Acute MI
Sotalol has been used in a controlled trial following an acute myocardial infarction without evidence of increased mortality (see Safety in Patients with Structural Heart Disease ). 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.
The following warnings are related to the beta-blocking activity of BETAPACE AF.
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, it is prudent when discontinuing chronically administered BETAPACE AF, particularly in patients with ischemic heart disease, to carefully monitor the patient and consider the temporary use of an alternate beta-blocker if appropriate. If possible, the dosage of BETAPACE AF 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 BETAPACE AF, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.
Non-Allergic Bronchospasm (e.g., chronic bronchitis and emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. It is prudent, if BETAPACE AF® (sotalol hydrochloride) is to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors may be minimized.
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.
Anesthesia
The management of patients undergoing major surgery who are being treated with beta-blockers is controversial. Protracted severe hypotension and difficulty in restoring and maintaining normal cardiac rhythm after anesthesia have been reported in patients receiving beta-blockers.
Diabetes
In patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia, BETAPACE AF should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.
Sick Sinus Syndrome
BETAPACE AF should be used only with extreme caution 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, the risk of Torsade de Pointes with BETAPACE AF therapy is increased, especially after cardioversion. Bradycardia following cardioversion in these patients is associated with QTc interval prolongation which is augmented due to the reverse use dependence of the Class III effects of BETAPACE AF. Patients with AFIB/AFL associated with the sick sinus syndrome may be treated with BETAPACE AF if they have an implanted pacemaker for control of bradycardia symptoms.
Thyrotoxicosis
Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. The beta-blocking effects of BETAPACE AF may be useful in controlling heart rate in AFIB associated with thyrotoxicosis but no study has been conducted to evaluate this.
PRECAUTIONS
Renal Impairment
BETAPACE AF (sotalol hydrochloride) 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 BETAPACE 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 BETAPACE 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 BETAPACE 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.
Medications and Supplements
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 BETAPACE AF such as other cardiac antiarrhythmic drugs, some phenothiazines, bepridil, tricyclic antidepressants and oral macrolides (see WARNINGS and 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 BETAPACE AF therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter medicine.
Electrolyte Imbalance
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.
Dosing Schedule
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.
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