Sotalol 80 mg Tablet, 60-count — NDC 71335-1189-1 (Billing 71335-1189-01)

12 CLINCAL PHARMACOLOGY

12.1Mechanism of Action Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day.

Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above. In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m 2 body surface area (BSA).

A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses ≥ 90 mg/m 2 in children.

12.2Pharmacodynamics Cardiac Electrophysiological Effects Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue. In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness.

The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio­ ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40–100 msec in QT and 10–40 msec in QT c [ See Warnings and Precautions (5.1) ]. No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with Sotalol Hydrochloride Tablets, the average defibrillatory threshold was 6 joules (range 2–15 joules) compared to a mean of 16 joules for a nonrandomized comparative group primarily receiving amiodarone. Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m 2 with dosing every 8 hours for a total 9 doses.

During steady-state, the respective average increases above baseline of the QT c interval were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%.

The smallest children (BSA<0.33 m 2 ) showed a tendency for larger Class III effects (ΔQT c ) and an increased frequency of prolongations of the QT c interval as compared with larger children (BSA ≥0.33 m 2 ). The beta-blocking effects also tended to be greater in the smaller children (BSA <0.33 m 2 ). Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentrations.

Hemodynamics In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of Sotalol Hydrochloride Tablets produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post- dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant increases of 25… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day.

Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above. In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m 2 body surface area (BSA).

A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses ≥ 90 mg/m 2 in children.

12.3Pharmacokinetics The pharmacokinetics of the d and l enantiomers of sotalol are essentially identical. Absorption In healthy subjects, the oral bioavailability of sotalol is 90–100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2–3 days (that is, after 5–6 doses when administered twice daily).

Over the dosage range 160–640 mg/day sotalol displays dose proportionality with respect to plasma concentrations. When administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to administration in fasting state. Distribution Sotalol does not bind to plasma proteins.

Distribution occurs to a central (plasma) and to a peripheral compartment. Sotalol crosses the blood brain barrier poorly. Metabolism Sotalol is not metabolized and is not expected to inhibit or induce any CYP450 enzymes.

Excretion Excretion of sotalol is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment [ see Dosage and Administration (2.5) ]. The mean elimination half- life of sotalol is 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.

Specific Populations Pediatric: The combined analysis of a single-dose study and a multiple-dose study with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/m 2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m 2 were administered every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on average between 2–3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours.

Steady-state was reached after 1–2 days. The average peak to trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol.

The smallest children (BSA<0.33m 2 ) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%. Geriatric: Age does not significantly alter the pharmacokinetics of Sotalol Hydrochloride Tablets, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation.

Renal Impairment: Sotalol 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. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients.

Doses or dosing intervals should be adjusted based on creatinine clearance [ see Dosage and Administration (2.5) ]. Hepatic Impairment: Patients with hepatic impairment show no alteration in clearance of sotalol. Drug-Drug Interactions: Antacids: Administration of oral sotalol within 2 hours of antacids 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 oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol. No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

12.2Pharmacodynamics Cardiac Electrophysiological Effects Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue. In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness.

The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio­ ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40–100 msec in QT and 10–40 msec in QT c [ See Warnings and Precautions (5.1) ]. No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with Sotalol Hydrochloride Tablets, the average defibrillatory threshold was 6 joules (range 2–15 joules) compared to a mean of 16 joules for a nonrandomized comparative group primarily receiving amiodarone. Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m 2 with dosing every 8 hours for a total 9 doses.

During steady-state, the respective average increases above baseline of the QT c interval were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%.

The smallest children (BSA<0.33 m 2 ) showed a tendency for larger Class III effects (ΔQT c ) and an increased frequency of prolongations of the QT c interval as compared with larger children (BSA ≥0.33 m 2 ). The beta-blocking effects also tended to be greater in the smaller children (BSA <0.33 m 2 ). Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentrations.

Hemodynamics In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of Sotalol Hydrochloride Tablets produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post- dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart failure.

Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by Sotalol Hydrochloride Tablets, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in patients with marginal cardiac compensation [ see Warnings and Precautions (5.3) ].

14 CLINICAL STUDIES

14.1Ventricular Arrhythmias Sotalol Hydrochloride Tablets have been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), Sotalol Hydrochloride Tablets were significantly superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the response was dose-related through 640 mg/day with 80–85% of patients having at least a 75% reduction of VPCs. Sotalol Hydrochloride Tablets were also superior, at the doses evaluated, to propranolol (40–80 mg TID) and similar to quinidine (200–400 mg QID) in reducing VPCs.

In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], Sotalol Hydrochloride Tablets were studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically. In a double-blind, randomized comparison of Sotalol Hydrochloride Tablets and procainamide given intravenously (total of 2 mg/kg Sotalol Hydrochloride vs. 19 mg/kg of procainamide over 90 minutes), Sotalol Hydrochloride Tablets suppressed PES induction in 30% of patients vs.

20% for procainamide (p=0.2). In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of Sotalol Hydrochloride Tablets was compared with that of 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine and pirmenol).

Overall response, limited to first randomized drug, was 39% for Sotalol Hydrochloride Tablets and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for Sotalol Hydrochloride Tablets vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), Sotalol Hydrochloride Tablets yielded 41% response vs.

45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), Sotalol Hydrochloride Tablets, when compared to the pool of other drugs, had the lowest two- year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs.

60%), and the lowest withdrawal rate (38% vs. about 75–80%). The most commonly used doses of Sotalol Hydrochloride Tablets in this trial were 320– 480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more. It cannot be determined, however, in the absence of a controlled comparison of Sotalol Hydrochloride Tablets vs. no pharmacologic treatment (for example, in patients with implanted defibrillators) whether Sotalol Hydrochloride Tablets response causes improved survival or identifies a population with a good prognosis.

Sotalol Hydrochloride Tablets have not been shown to enhance survival in patients with ventricular arrhythmias.

14.3Clinical Studies in Patients with Myocardial Infarction In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456); Sotalol Hydrochloride Tablets were given as a non-titrated initial dose of 320 mg once daily. Sotalol Hydrochloride Tablets did not produce a significant increase in survival (7.3% mortality on Sotalol Hydrochloride Tablets vs. 8.9% on placebo, p=0.3), but overall did not suggest an adverse effect on survival.

There was, however, a suggestion of an early (i.e., first 10 days) excess mortality (3% on Sotalol Hydrochloride Tablets vs. 2% on placebo). In a second small trial (n=17 randomized to Sotalol Hydrochloride Tablets) where Sot… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, 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/m 2 ) 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/m 2 ). 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 18 times the MRHD as mg/m2) prior to mating, except for a small reduction in the number of offspring per litter.

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 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/m 2 ) produced a slight increase in fetal death, and 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 HCl, 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.