Sotalol hydrochloride tablets, USP are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of sotalol hydrochloride tablets, USP (see WARNINGS ), including a 1.5 to 2% rate of Torsade de Pointes or new VT/VF in patients with either NSVT or supraventricular arrhythmias, its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended.
Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Initiation of sotalol hydrochloride treatment or increasing doses, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. The response to treatment should then be evaluated by a suitable method (e.g., PES or Holter monitoring) prior to continuing the patient on chronic therapy.
Various approaches have been used to determine the response to antiarrhythmic therapy, including sotalol hydrochloride tablets, USP. In the ESVEM Trial, response by Holter monitoring was tentatively defined as 100% suppression of ventricular tachycardia, 90% suppression of nonsustained VT, 80% suppression of paired VPCs, and 75% suppression of total VPCs in patients who had at least 10 VPCs/hour at baseline; this tentative response was confirmed if VT lasting 5 or more beats was not observed during treadmill exercise testing using a standard Bruce protocol.
The PES protocol utilized a maximum of three extrastimuli at three pacing cycle lengths and two right ventricular pacing sites. Response by PES was defined as prevention of induction of the following: 1) monomorphic VT lasting over 15 seconds; 2) non-sustained polymorphic VT containing more than 15 beats of monomorphic VT in patients with a history of monomorphic VT; 3) polymorphic VT or VF greater than 15 beats in patients with VF or a history of aborted sudden death without monomorphic VT; and 4) two episodes of polymorphic VT or VF of greater than 15 beats in a patient presenting with monomorphic VT.
Sustained VT or NSVT producing hypotension during the final treadmill test was considered a drug failure. In a multicenter open-label long-term study of sotalol in patients with life-threatening ventricular arrhythmias which had proven refractory to other antiarrhythmic medications, response by Holter monitoring was defined as in ESVEM. Response by PES was defined as non-inducibility of sustained VT by at least double extrastimuli delivered at a pacing cycle length of 400 msec.
Overall survival and arrhythmia recurrence rates in this study were similar to those seen in ESVEM, although there was no comparative group to allow a definitive assessment of outcome. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias. Sotalol is also 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 and is marketed under the brand name Betapace AF (sotalol hydrochloride, tablets, USP).
Sotalol hydrochloride tablets, USP is not approved for the AFIB/AFL indication and should not be substituted for Betapace AF because only Betapace AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.
Contraindications
Sotalol hydrochloride is contraindicated in patients with bronchial asthma, sinus bradycardia, second and third degree AV block, unless a functioning pacemaker is present, congenital or acquired long QT syndromes, cardiogenic shock, uncontrolled congestive heart failure, and previous evidence of hypersensitivity to sotalol.
Warnings and precautions
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 asymptomatic, 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 associated with 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 hydrochloride 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 Studies ).
On the other hand, in the large postinfarction 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 the 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 QTc a (msec) 80 0 (69) b 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) a) highest on-therapy value 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 (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 QT c is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QT c exceeds 550 msec. Due to the multiple risk factors associated with Torsade de Pointes, however, caution should be exercised regardless of the QT c interval.
The table below relates the incidence of Torsade de Pointes to on-therapy QT c and change in QTc 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 . Relationship Between QTc Interval Prolongation and Torsade de Pointes ( ) Number of patients assessed On-Therapy QTc Interval (msec) Incidence of Torsade de Pointes Change in QTc Interval From Baseline (msec) Incidence of Torsade de Pointes < 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
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
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.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. 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 C max 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.
Pregnancy and breastfeeding
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/m 2 ), respectively, did not reveal any teratogenic potential associated with sotalol hydrochloride. In rabbits, a high dose of sotalol hydrochloride (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m 2 ) 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/m 2 ) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol hydrochloride, 100 times the MRHD (18 times the MRHD as mg/m 2 ), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m 2 ), 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 hydrochloride 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 hydrochloride tablets should be used during pregnancy only if the potential benefit outweighs the potential risk.
Adverse reactions
During premarketing trials, 3186 patients with cardiac arrhythmias (1363 with sustained ventricular tachycardia) received oral sotalol, of whom 2451 received the drug for at least two weeks. The most important adverse effects are Torsade de Pointes and other serious new ventricular arrhythmias (see WARNINGS ), occurring at rates of almost 4% and 1%, respectively, in the VT/VF population. Overall, discontinuation because of unacceptable side-effects was necessary in 17% of all patients in clinical trials, and in 13% of patients treated for at least two weeks.
The most common adverse reactions leading to discontinuation of sotalol are as follows: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. Occasional reports of elevated serum liver enzymes have occurred with sotalol therapy but no cause and effect relationship has been established. 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.
In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 2 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/m 2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 2 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/m 2 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. Potential Adverse Effects Foreign marketing experience with sotalol hydrochloride shows an adverse experience 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 lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, alopecia. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been associated with sotalol during investigational use and foreign marketing experience.
Composition
Active ingredients
SOTALOL HYDROCHLORIDE 160MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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