SOTALOL HYDROCHLORIDE- sotalol hydrochloride tablet
Epic Pharma, LLC
To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets (AF) should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring and calculations of creatinine clearance. For detailed instructions regarding dose selection, and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the treatment of documented life-threatening ventricular arrhythmias and is marketed under the brand name Betapace ® (sotalol hydrochloride tablets). Sotalol hydrochloride tablets however, should not be substituted for sotalol hydrochloride tablets (AF) because of significant differences in labeling (i.e. patient package insert, dosing administration and safety information).
Sotalol hydrochloride tablets, USP (AF) are an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a white, capsule-shaped tablet for oral administration. Sotalol hydrochloride 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 is d, l- N -[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl] methanesulfonamide monohydrochloride. The molecular formula is C 12 H 20 N 2 O 3 S•HCl and is represented by the following structural formula:
Sotalol hydrochloride tablets, USP (AF) contain the following inactive ingredients: pregelatinized starch, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, stearic acid, and magnesium stearate.
Sotalol hydrochloride has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol hydrochloride is a racemic mixture of d- and l-sotalol. Both isomers 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 electrophysiological 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.
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 (AF) 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 . In a study of patients with atrial fibrillation (AFIB)/flutter (AFIB/AFL) receiving three different oral doses of sotalol hydrochloride (AF) given q12h (or q24h in patients with a reduced creatinine clearance), mean increases in QT intervals measured from 12-lead ECGs of 25 msec, 40 msec and 54 msec were found in the 80 mg, 120 mg, and 160 mg dose groups, respectively. (See WARNINGS for description of relationship between QT c 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, the average defibrillatory threshold was 6 joules (range 2-15 joules) compared to a mean of 16 joules for a non-randomized comparative group primarily receiving amiodarone.
In a dose-response trial comparing three dose levels of sotalol hydrochloride 80 mg, 120 mg, and 160 mg with placebo given q12h (or q24h in patients with a reduced renal creatinine clearance) for the prevention of recurrence of symptomatic atrial fibrillation (AFIB)/flutter (AFL), the mean ventricular rate during recurrence of AFIB/AFL was 125, 107, 110 and 99 beats/min in the placebo, 80 mg, 120 mg and 160 mg dose groups, respectively (p<0.017 for each sotalol dose group versus placebo). In another placebo controlled trial in which sotalol hydrochloride was titrated to a dose between 160 and 320 mg/day in patients with chronic AFIB, the mean ventricular rate during recurrence of AFIB was 107 and 84 beats/min in the placebo and sotalol hydrochloride groups, respectively (p<0.001).
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, 90 and 210 mg/m 2 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QT c 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 QT c 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<0.33m 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 the larger children (BSA ≥0.33m 2). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33m 2). Both the Class III and beta-blocking effects of sotalol were linearly related with the plasma concentrations.
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 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, 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, caution should be exercised in patients with marginal cardiac compensation as deterioration in cardiac performance may occur. (See WARNINGS: Congestive Heart Failure. )
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