Sotalol Information
Sotalol ()
Sotalol ()
Sotalol () Description
Sotalol () hydrochloride, is 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 tablets (AF) is d,l-N-[4-[l-hydroxy-2-[(l-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is CHNOS•HCl and is represented by the following structural formula:
Each tablet contains 80 mg, 120 mg, or 160 mg of Sotalol () hydrochloride. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, corn starch, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, stearic acid.
Sotalol () Clinical Pharmacology
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 tablets (AF) 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 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 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 () 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. In a study of patients with atrial fibrillation (AFIB)/flutter (AFIB/AFL) receiving three different oral doses of Sotalol () 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 for 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 () 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 tablets (AF), 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
Twenty-five children in an unblended, 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 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QT 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 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
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 .).
In healthy subjects, the oral bioavailability of Sotalol () is 90 to 100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 to 3 days (i.e., after 5 to 6 doses when administered twice daily). Over the dosage range 160 to 640 mg/day Sotalol () displays dose proportionality with respect to plasma concentrations. Distribution occurs to a central (plasma) and to a peripheral compartment, with a mean elimination half-life of 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.
Sotalol () does not bind to plasma proteins and is not metabolized. Sotalol () shows very little intersubject variability in plasma levels. The pharmacokinetics of the d and l enantiomers of Sotalol () are essentially identical. Sotalol () crosses the blood brain barrier poorly. Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment (see ). Age per se does not significantly alter the pharmacokinetics of Sotalol () , but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation. The absorption of Sotalol () was reduced by approximately 20% compared to fasting when it was administered with a standard meal. Since Sotalol () is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of Sotalol () .
The combined analyses of two unblended, multicenter trials (a single dose 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 of Sotalol () was administered in the single dose study and daily doses of 30, 90 and 210 mg/m were administered q8h in the multi-dose study. After rapid absorption with peak levels occurring on average between 2 to 3 hours following administration, Sotalol () was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 to 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
Sotalol () Indications And Usage
Sotalol () hydrochloride tablets (AF) are 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. Because Sotalol () hydrochloride tablets (AF) can cause life-threatening ventricular arrhythmias, it should be reserved for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB/AFL that is easily reversed (by Valsalva maneuver, for example) should usually not be given Sotalol () hydrochloride tablets (AF) (See ).
In general, antiarrhythmic therapy for AFIB/AFL aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients (See ).
Sotalol () is also indicated for the treatment of documented life-threatening ventricular arrhythmias and is marketed under the brand name BETAPACE (Sotalol () hydrochloride). BETAPACE, however, must 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 () Contraindications
Sotalol () hydrochloride tablets is contraindicated in patients with sinus bradycardia ( 450 msec, cardiogenic shock, uncontrolled heart failure, hypokalemia (
Sotalol () Warnings
Sotalol () hydrochloride tablets (AF) can cause serious ventricular arrhythmias, primarily torsade de pointes (tdp) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to the dose of Sotalol () hydrochloride tablets (AF). Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of tdp. The risk of tdp can be reduced by adjustment of the Sotalol () hydrochloride tablets (AF) dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
Treatment with Sotalol () hydrochloride tablets (AF) must therefore be started only in patients observed for a minimum of three days on their maintenance dose in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance must precede administration of the first dose of Sotalol () hydrochloride tablets (AF). For detailed instructions regarding dose selection, see .
In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of torsade de pointes reported (0.6%) during the controlled phase of treatment with Sotalol () hydrochloride tablets (AF). The incidence of torsade de pointes was significantly lower in those patients receiving total daily doses of 320 mg or less (0.3%), as summarized in Table 5 below. Both patients who had torsade de pointes in the group receiving > 320 mg/day were receiving 640 mg/day. In the group receiving ≤ 320 mg daily, one case of tdp occurred at a daily dose of 320 mg on day 4 of treatment and one case occurred on a daily dose of 160 mg on day 1 of treatment.
Prolongation of the QT interval is dose related, increasing from baseline an average of 25, 40, and 50 msec in the 80, 120, and 160 mg groups, respectively, in the clinical dose-response study. In this clinical trial Sotalol () hydrochloride tablets (AF) treatment was not initiated if the QT interval was greater than 450 msec and during therapy the dose was reduced or discontinued if the QT interval was ≥ 520 msec.
Experience in patients with ventricular arrhythmias is also pertinent to the risk of torsade de pointes in patients with AFIB/AFL (see below).
In patients with a history of sustained ventricular tachycardia, the incidence of torsade de pointes during Sotalol () treatment was 4% and worsened VT in about 1%; in patients with other less serious ventricular arrhythmias the incidence of torsade de pointes was 1% and new or worsened VT in about 0.7%. 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.
Torsade de pointes arrhythmias in patients with VT/VF were dose related, as was the prolongation of QT (QT) interval, as shown in Table 6 below.
Table 7 below relates the incidence of torsade de pointes to on-therapy QT and change in QT from baseline. It should be noted, however, that the highest on-therapy QT 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.
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 interval 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 ventricular arrhythmia 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 ). 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.
Sotalol () has been used in a controlled trial following an acute myocardial infarction without evidence of increased mortality (see ). Although specific studies of its use in treating atrial arrhythmias after infarction have not been conducted, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia or prolonged QT interval apply.
The following warnings are related to the beta-blocking activity of Sotalol () hydrochloride tablets (AF).
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS.
2
Sotalol () Precautions
Sotalol () hydrochloride tablets (AF) is eliminated principally 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 () hydrochloride tablets (AF). Guidance for dosing in conditions of renal impairment can be found under "."
Please refer to the patient package insert.
Prior to initiation of Sotalol () hydrochloride tablets (AF) therapy, the patient should be advised to read the patient package insert and reread it each time therapy is renewed. The patient should be fully instructed on the need for compliance with the recommended dosing of Sotalol () hydrochloride tablets (AF), the potential interactions with drugs that prolong the QT interval and other antiarrhythmics, and the need for periodic monitoring of QT and renal function to minimize the risk of serious abnormal rhythms.
No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 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) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m).
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 9 times the MRHD as mg/m) 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), 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) 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) 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), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m), 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 () HCl 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 (AF) should be used during pregnancy only if the potential benefit outweighs the potential risk.
Sotalol () Adverse Reactions
Adverse events that are clearly related to Sotalol () are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects. The common documented beta-blocking adverse events (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related.
In a pooled clinical trial population consisting of four placebo-controlled studies with 275 patients with AFIB/AFL treated with 160 to 320 mg doses of Sotalol () hydrochloride tablets (AF), the following adverse events were reported at a rate of 2% or more in the 160 to 240 mg treated patients and greater than the rate in placebo patients (see Table 8). The data are presented by incidence of events in the Sotalol () hydrochloride tablets (AF) and placebo groups by body system and daily dose. No significant irreversible non-cardiac end-organ toxicity was observed.
Overall, discontinuation because of unacceptable adverse events was necessary in 17% of the patients, and occurred in 10% of patients less than two weeks after starting treatment. The most common adverse events leading to discontinuation of Sotalol () hydrochloride tablets (AF) were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.
In clinical trials involving 1292 patients with sustained VT/VF, the common adverse events (occurring in ≥ 2% of patients) were similar to those described for the AFIB/AFL population.
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.
In an unblinded multicenter trial of 25 pediatric patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 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 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 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≥ 525 msec were seen in 2 patients at the 210 mg/m daily dose level. Serious adverse events including death, torsades de pointe, other proarrhythmias, high-degree A-V blocks and bradycardia have been reported in infants and/or children.
Sotalol () Overdosage
Intentional or accidental overdosage with Sotalol () has rarely resulted in death.
Sotalol () Dosage And Administration
Step 1.
Step 2:
creatinine clearance (male) = 72 × serum creatinine (mg/dL)
creatinine clearance (female) = 72 × serum creatinine (mg/dL)
When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L)
Step 3.
Step 4.
Step 5.
In patients with a creatinine clearance of 40 to 60 mL/min, if the 80 mg daily dose (administered as 80 mg QD or 40 mg BID) is tolerated and the QT interval remains
The steps described above are summarized in the following diagram:
The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 160 mg BID, doses greater than 160 mg BID have been associated with an increased incidence of torsade de pointes and are not recommended.
A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time.
As in adults the following precautionary measures should be considered when initiating Sotalol () treatment in children: initiation of treatment in the hospital after appropriate clinical assessment: individualization regimen as appropriate: gradual increase of doses if required: careful assessment of therapeutic response and tolerability: and frequent monitoring of the QT interval heart rate.
For initiation of treatment, 30 mg/m three times a day (90 mg/m total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QT, with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady-state plasma concentrations of Sotalol () in patients with age-adjusted normal renal function.
For children aged about 2 years or younger
For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 × 0.97) =29.1 mg/m, administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 × 0.68) = 20 mg/m, administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 × 0.3)=9 mg/m. Similar calculations should be made for increased doses as titration proceeds. Since the half-life of Sotalol () decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer.
In all children, individualization of dosage is required. As in adults Sotalol () hydrochloride should be used with particular caution in children if the QT is greater than 500 msec on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when QT, exceeds 550 msec.
The use of Sotalol () hydrochloride AF in children with renal impairment has not been investigated. Sotalol () elimination is predominantly via the kidney in the unchanged form. Use of Sotalol () in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QT is more important and it will take much longer to reach steady-state with any dose and/or frequency of administration.
Sotalol () Hydrochloride Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) available from Humco Laboratories as follows:
The endpoint is achieved when a dispersion of fine particles in the syrup is obtained.
This compounding procedure results in a solution containing 5 mg/mL of Sotalol () HCl. The fine solid particles are the water-insoluble inactive ingredients of the tablets.
This extemporaneously prepared oral solution of Sotalol () HCl (with suspended inactive particles) must be shaken well prior to administration. This is to ensure that the amount of inactive solid particles per dose remains constant throughout the duration of use.
Stability studies indicate that the suspension is stable when stored at controlled room temperature (15°-30°C/59°-86°F) and ambient humidity for three (3) months.
Sotalol () How Supplied
Sotalol () hydrochloride tablets (AF), 80 mg, oval white, scored, debossed MP 518 on one side, the other side plain.
Bottles of 30 unit of use NDC 53489-503-07Bottles of 60 unit of use NDC 53489-503-06Bottles of 100 NDC 53489-503-01Bottles of 250 NDC 53489-503-03Bottles of 500 NDC 53489-503-05Bottles of 1000 NDC 53489-503-10
Sotalol () hydrochloride tablets (AF), 120 mg, oval white, scored, debossed MP 519 on one side, the other side plain.
Bottles of 30 unit of use NDC 53489-504-07Bottles of 60 unit of use NDC 53489-504-06Bottles of 100 NDC 53489-504-01Bottles of 250 NDC 53489-504-03Bottles of 500 NDC 53489-504-05Bottles of 1000 NDC 53489-504-10
Sotalol () hydrochloride tablets (AF), 160 mg, oval white, scored, debossed MP 520 on one side, the other side plain.
Bottles of 30 unit of use NDC 53489-505-07Bottles of 60 unit of use NDC 53489-505-06Bottles of 100 NDC 53489-505-01Bottles of 250 NDC 53489-505-03Bottles of 500 NDC 53489-505-05Bottles of 1000 NDC 53489-505-10
Sotalol ()
