Sotalol Hydrochloride

SOTALOL HYDROCHLORIDE — sotalol hydrochloride tablet
Physicians Total Care, Inc.

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

DESCRIPTION

Sotalol hydrochloride USP is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a light-blue, capsule-shaped tablet for oral administration. Sotalol hydrochloride USP is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride USP is d,l-N -[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12 H20 N2 O3 S•HCl and is represented by the following structural formula:

Chemical Structure
(click image for full-size original)

Each sotalol hydrochloride tablet USP, for oral administration, contains 80 mg, 120 mg, 160 mg or 240 mg of sotalol hydrochloride. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, FD&C blue No. 1 aluminum lake, hydroxypropyl cellulose, lactose anhydrous, lactose monohydrate, magnesium stearate, pregelatinized starch and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Sotalol hydrochloride tablets have both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol hydrochloride tablets are a racemic mixture of d- and l-sotalol. Both isomers have similar Class III antiarrhythmic effects, while the I-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 mg/day 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/m2 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/m2 in children.

Electrophysiology

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 hydrochloride tablets 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 mg/day to 640 mg/day, the surface ECG shows dose-related mean increases of 40 msec to 100 msec in QT and 10 msec to 40 msec in QTc . (See WARNINGSfor description of relationship between QTc and torsade de pointes type arrhythmias.) 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 joules to 15 joules) compared to a mean of 16 joules for a non-randomized comparative group primarily receiving amiodarone.

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30 mg/m2 , 90 mg/m2 and 210 mg/m2 with dosing every 8 hours for a total 9 doses. During steady-state, the respective average increases above baseline of the QTc interval, in msec (%), were 2(+1%), 14(+4%) and 29(+7%) msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval, in msec (%), were 23(+6%), 36(+9%) and 55(+14%) msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3%, 9% and 12%. The smallest children (BSA< 0.33m2) showed a tendency for larger Class III effects (ΔQTc ) and an increased frequency of prolongations of the QTc interval as compared with larger children (BSA≥0.33m2). The beta-blocking effects also tended to be greater in the smaller children (BSA< 0.33m2). Both the Class III and beta-blocking effects of sotalol were linearly related with 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 non-significant increases of 25% and 8%, respectively. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. One patient was discontinued because of worsening congestive heart failure. 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 hydrochloride tablets produces significant reductions in both systolic and diastolic blood pressures. Although sotalol hydrochloride tablets are usually well-tolerated hemodynamically, caution should be exercised in patients with marginal cardiac compensation as deterioration in cardiac performance may occur (see WARNINGS, Congestive Heart Failure).

Clinical Actions

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% to 85% of patients having at least a 75% reduction of VPCs. Sotalol hydrochloride tablets were also superior at the doses evaluated, to propranolol (40 mg to 80 mg TID) and similar to quinidine (200 mg to 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 tablets 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 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine and pirmenol). Overall response, limited to first randomized drug, was 39% for sotalol 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% to 80%). The most commonly used doses of sotalol hydrochloride tablets in this trial were 320 mg/day to 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 (e.g., in patients with implanted defibrillators) whether sotalol hydrochloride tablet response causes improved survival or identifies a population with a good prognosis.

In a large double-blind, placebo controlled secondary prevention (post-infarction) 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 vs. 2% on placebo). In a second small trial (n=17 randomized to sotalol) where sotalol was administered at high doses (e.g., 320 mg twice daily) to high-risk post-infarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol.

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