Sotalol Hydrochloride 80 mg Tablet, 90-count — NDC 63187-804-90 (Billing 63187-0804-90)

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 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, deat… [Excerpted — this section continues on DailyMed.]

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.

Elevated blood glucose levels and increased insulin requirements can occur in diabetic patients. The following table lists as a function of dosage the most common (incidence of 2% or greater) adverse events, regardless of relationship to therapy and the percent of patients discontinued due to the event, as collected from clinical trials involving 1292 patients with sustained VT/VF. Incidence (%) of Adverse Events and Discontinuations DAILY DOSE Body System 160 mg (n = 832) 240 mg (n = 263) 320 mg (n = 835) 480 mg (n = 459) 640 mg (n = 324) Any Dose a (n = 1292) % Patients Discontinued (n = 1292) Body as a whole infection 1 2 2 2 3 4 < 1 fever 1 2 3 2 2 4 < 1 localized pain 1 1 2 2 2 3 < 1 Cardiovascular dyspnea 5 8 11 15 15 21 2 bradycardia 8 8 9 7 5 16 2 chest pain 4 3 10 10 14 16 < 1 palpitation 3 3 8 9 12 14 < 1 edema 2 2 5 3 5 8 1 ECG abnormal 4 2 4 2 2 7 1 hypotension 3 4 3 2 3 6 2 proarrhythmia < 1 < 1 2 4 5 5 3 syncope 1 1 3 2 5 5 1 heart failure 2 3 2 2 2 5 1 presyncope 1 2 2 4 3 4 < 1 peripheral vascular disorder 1 2 1 1 2 3 < 1 cardiovascular disorder 1 < 1 2 2 2 3 < 1 vasodilation 1 < 1 1 2 1 3 < 1 AICD discharge < 1 2 2 2 2 3 < 1 hypertension < 1 1 1 1 2 2 < 1 Nervous fatigue 5 8 12 12 13 20 2 dizziness 7 6 11 11 14 20 1 asthenia 4 5 7 8 10 13 1 light-headed 4 3 6 6 9 12 1 headache 3 2 4 4 4 8 < 1 sleep problem 1 1 5 5 6 8 < 1 perspiration 1 2 3 4 5 6 < 1 altered consciousness 2 3 1 2 3 4 < 1 depression 1 2 2 2 3 4 < 1 paresthesia 1 1 2 3 2 4 < 1 anxiety 2 2 2 3 2 4 < 1 mood change < 1 < 1 1 3 2 3 < 1 appetite disorder 1 2 2 1 3 3 < 1 stroke < 1 < 1 1 1 < 1 1 < 1 Digestive nausea/vomiting 5 4 4 6 6 10 1 diarrhea 2 3 3 3 5 7 < 1 dyspepsia 2 3 3 3 3 6 < 1 abdominal pain < 1 < 1 2 2 2 3 < 1 colon problem 2 1 1 < 1 2 3 < 1 flatulence 1 < 1 1 1 2 2 < 1 Respiratory pulmonary problem 3 3 5 3 4 8 < 1 upper respiratory tract problem 1 1 3 4 3 5 < 1 asthma 1 < 1 1 1 1 2 < 1 Urogenital genitourinary disorder 1 0 1 1 2 3 < 1 sexual dysfunction < 1 1 1 1 3 2 < 1 Metabolic abnormal lab value 1 2 3 2 1 4 < 1 weight change 1 1 1 < 1 2 2 < 1 Musculoskeletal extremity pain 2 2 4 5 3 7 < 1 back pain 1 < 1 2 2 2 3 < 1 Skin and Appendages rash 2 3 2 3 4 5 < 1 Hematologic bleeding 1 < 1 1 < 1 2 2 < 1 Special Senses visual problem 1 1 2 4 5 5 < 1 a) Because patients are counted at each dose level tested, the Any Dose column cannot be determined by adding across the doses.

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),… [Excerpted — this section continues on DailyMed.]

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.

PRECAUTIONS Renal Impairment Sotalol hydrochloride is mainly eliminated 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. 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 urin… [Excerpted — this section continues on DailyMed.]