WARNINGS
Mortality
The National Heart, Lung, And Blood Institute's Cardiac Arrhythmia Suppression Trial I (CAST I) was a long-term, multi-center double-blind study in patients with symptomatic, non-life-threatening ventricular arrhythmias, 1 to 103 weeks after acute myocardial infarction. Patients in CAST I were randomized to receive placebo or individually optimized doses of encainide, flecainide, or moricizine. The Cardiac Arrhythmia Suppression Trial II (CAST II) was similar, except that the recruited patients had had their index infarction 4 to 90 days before randomization, patients with left ventricular ejection fractions greater than 40% were not admitted, and the randomized regimens were limited to placebo and moricizine.
CAST I was discontinued after an average time-on-treatment of 10 months, and CAST II was discontinued after an average time-on-treatment of 18 months. As compared to placebo treatment, all three active therapies were associated with increases in short-term (14 day) mortality, and encainide and flecainide were associated with significant increases in longer-term mortality as well. The longer-term mortality rate associated with moricizine treatment could not be statistically distinguished from that of placebo.
The applicability of these results to other populations (e.g., those without recent myocardial infarction) and to other than Class I antiarrhythmic agents is uncertain. Sotalol is devoid of Class I effects, and in a large (n=1,456) controlled trial in patients with a recent myocardial infarction, who did not necessarily have ventricular arrhythmias, sotalol did not produce increased mortality at doses up to 320 mg/day (see Clinical Actions). On the other hand, in the large post-infarction study using a non-titrated initial dose of 320 mg once daily and in a second small randomized trial in high-risk post-infarction patients treated with high doses (320 mg BID), there have been suggestions of an excess of early sudden deaths.
Proarrhythmia
Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization (QTc interval prolongation), torsade de pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis is the most common form of proarrhythmia associated with sotalol, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of torsade de pointes progressively increases with prolongation of QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (See Electrolyte Disturbances.)
Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and the patient's underlying rhythm disorder. (Note, however, that torsade de pointes is usually a drug-induced arrhythmia in people with an initially normal QTc). Thus, the incidence of drug-related events cannot be precisely determined, so that the occurrence rates provided must be considered approximations. Note also that drug-induced arrhythmias may often not be identified, particularly if they occur long after starting the drug, due to less frequent monitoring. It is clear from the NIH-sponsored CAST (see WARNINGS: Mortality) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole, that do not appear early in treatment but that represent a sustained increased risk.
Overall in clinical trials with sotalol, 4.3% of 3257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular tachycardia in approximately 1% of patients and torsade de pointes in 2.4%. 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. In patients with a history of sustained ventricular tachycardia, the incidence of torsade de pointes was 4% and worsened VT in about 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of torsade de pointes was 1% and 1.4%, respectively.
Torsade de pointes arrhythmias were dose related, as is the prolongation of QT (QTc) interval, as shown in the table below.
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 QTchighest on-therapy value (msec) |
|---|
| () number of patients assessed |
| 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) |
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 (see table below) 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 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.
Nonetheless, sotalol should be used with particular caution if the QTc is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc exceeds 550 msec. Due to the multiple risk factors associated with torsade de pointes, however, caution should be exercised regardless of the QTc interval. The table 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.
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 |
|---|
| () Number of patients assessed |
| <500 | 1.3% (1787) | | <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) |
Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (torsade de pointes and worsened VT) occurred within 7 days of initiating sotalol therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg BID with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of sotalol in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION).
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 congestive heart failure controlled by digitalis and/or diuretics, sotalol 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 premarketing 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
Sotalol 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.
Conduction Disturbances
Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be avoided (see Proarrhythmias above). Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of torsade de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.
Recent Acute MI
Sotalol can be used safely and effectively in the long-term treatment of life-threatening ventricular arrhythmias following a myocardial infarction. However, experience in the use of sotalol to treat cardiac arrhythmias in the early phase of recovery from acute MI is limited and at least at high initial doses is not reassuring. (See WARNINGS: Mortality.) In the first 2 weeks post-MI caution is advised and careful dose titration is especially important, particularly in patients with markedly impaired ventricular function.
The following warnings are related to the beta-blocking activity of sotalol.
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 sotalol, 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 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.
Non-Allergic Bronchospasm (e.g., chronic bronchitis and emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. It is prudent, if sotalol 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, sotalol should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.
Sick Sinus Syndrome
Sotalol 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.
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.
PRECAUTIONS
Renal Impairment
Sotalol is mainly 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. Guidance for dosing in conditions of renal impairment can be found under "DOSAGE AND ADMINISTRATION."
Drug Interactions
Drugs undergoing CYP450 metabolism
Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes.
Antiarrhythmics
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). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with sotalol.
Digoxin
Single and multiple doses of sotalol do not substantially affect serum digoxin levels. 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 CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin.
Calcium blocking drugs
Sotalol should be administered with caution in conjunction with calcium blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to hypotension.
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. Patients treated with sotalol plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and or marked bradycardia which may produce syncope.
Insulin and oral antidiabetics
Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked.
Beta-2-receptor stimulants
Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol.
Clonidine
Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving sotalol.
Other
No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.
Antacids
Administration of 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 sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.
Drugs prolonging the QT interval
Sotalol should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see WARNINGS).
DRUG/Laboratory Test Interactions
The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines.
Carcinogenesis, Mutagenicity, 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.
Pregnancy Category B
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.
Although there are no adequate and well-controlled studies in pregnant women, sotalol HCl has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with sotalol. Therefore, sotalol should be used during pregnancy only if the potential benefit outweighs the potential risk.
Nursing Mothers
Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from sotalol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of sotalol in pediatric patients have not been established. However, information relating to the clinical pharmacology in pediatric patients is approved for Berlex Laboratories' sotalol hydrochloride tablets. Due to Berlex's marketing exclusivity rights, this drug product is not labeled for pediatric use.
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