Black Box Warning: Life Threatening Proarrhythmia

Composition

SOTALAR 40

Each tablet contains sotalol hydrochloride………… 40 mg

Dosage Forms

Tablet

Pharmacology

Pharmacodynamics

Sotalol is an antiarrhythmic drug with Vaughan Williams Class II (beta-adrenoreceptor blocking) and Vaughan Williams Class III (cardiac action potential duration prolongation) 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 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 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 to 100 msec in QT and 10 to 40 msec in QTc. 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 nonrandomized 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, 90 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 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 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 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.

Clinical Studies

Sotalol has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), sotalol was 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 was 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 was 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 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 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 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 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, 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 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 vs. no pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol 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 was given as a non-titrated initial dose of 320 mg once daily. Sotalol did not produce a significant increase in survival (7.3% mortality on sotalol 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.

Pharmacokinetics

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 (i.e., 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

Distribution occurs to a central (plasma) and to a peripheral compartment; there is very little inter-subject variability in plasma levels. Sotalol crosses the blood brain barrier poorly, with cerebrospinal fluid concentrations only 10% of those in plasma.

Metabolism

Sotalol does not bind to plasma proteins and is not metabolized. Sotalol is not expected to inhibit or induce any CYP450 enzymes.

Excretion

Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment. The mean elimination half-life of sotalol is12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.

Special Population

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 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m 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) 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, although impaired renal function in geriatric patients can decrease the excretion rate, resulting in increased drug accumulation.

Renal Impairment

Impaired renal function can decrease the excretion rate, resulting in increased drug accumulation. Lower doses are necessary in conditions of renal impairment.

Hepatic Impairment: Patients with hepatic impairment show no alteration in the clearance of sotalol as it is not subject to first-pass metabolism.

Indications

Life-Threatening Ventricular Arrhythmias

SOTALAR is indicated for the treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia (VT), and symptomatic non-sustained ventricular tachyarrhythmias.

Supraventricular Arrhythmias

• Prophylaxis of paroxysmal atrial tachycardia, paroxysmal atrial fibrillation, paroxysmal A-V nodal re-entrant tachycardia, paroxysmal A-V re-entrant tachycardia using accessory pathways, and paroxysmal supraventricular tachycardia after cardiac surgery
• Maintenance of normal sinus rhythm following conversion of atrial fibrillation or atrial flutter

• Because SOTALAR can cause life-threatening ventricular arrhythmias, reserve its use for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB that is easily reversed (by Valsalva maneuver, for example) should usually not be given SOTALAR. 

Dosage and Administration

General Safety Measures for Initiation of Oral Sotalol Therapy

Other anti-arrhythmic therapy should be withdrawn before starting SOTALAR and monitor carefully for a minimum of 2 to 3 plasma half-lives if the patient’s clinical condition permits.

Hospitalize patients initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate oral sotalol therapy in the presence of personnel trained in the management of serious arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval (insert cross ref to renal dosing). Continually monitor patients with each uptitration in dose, until they reach steady state. Determine QTc 2 to 4 hours after every dose.

Discharge patients on sotalol therapy from an in-patient setting with an adequate supply of sotalol to allow uninterrupted therapy until the patient can fill a sotalol prescription.

Advise patients who miss a dose to take the next dose at the usual time. Do not double the dose or shorten the dosing interval.

General

The recommended initial dose of SOTALAR is 80 mg twice daily.

Adult Dose for Ventricular Arrhythmias

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see WARNINGS AND PRECAUTIONS]. Continually monitor patients until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses (because of the long terminal elimination half-life of sotalol, dosing more than a two times a day is usually not necessary). Oral doses as high as 480-640 mg/day have been utilized in patients with refractory life-threatening arrhythmias.

Adult Dose for Prevention of Recurrence of AFIB/AFL

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see WARNINGS AND PRECAUTIONS].  Continually monitor patients until steady state blood levels are achieved. Most patients will have satisfactory response with 120 mg twice daily. Initiation of sotalol in patients with creatinine clearance < 40 ml/min or QTc >450 is contraindicated [see CONTRAINDICATION].

Renal Impairment

Because sotalol is excreted mainly in urine, and its terminal elimination half-life is prolonged in conditions of renal impairment, the dosing interval (time between divided doses) of SOTALAR should be modified (when creatinine clearance is lower than 60 mL/min) according to Table 1 and Table 2:

* The initial dose of 80 mg and subsequent doses should be administered at these intervals.

* The initial dose of 80 mg and subsequent doses should be administered at these intervals

Since the terminal elimination half-life of sotalol is increased in patients with renal impairment, a longer duration of dosing is required to reach steady-state. Dose escalations in renal impairment should be done after administration of at least 5-6 doses at appropriate intervals (see table above). Extreme caution should be exercised in the use of SOTALAR in patients with renal failure undergoing hemodialysis. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Sotalol, however, can be partly removed by dialysis with subsequent partial rebound in concentrations when dialysis is completed. Both safety (heart rate, QT interval) and efficacy (arrhythmia control) must be closely monitored.

Contraindications

SOTALAR is contraindicated in patients with

• Bronchial asthma or related bronchospastic conditions
• Sinus bradycardia, sick sinus syndrome
• Second and third degree AV block, unless a functioning pacemaker is present
• Congenital or acquired long QT syndromes
• Cardiogenic shock or decompensated heart failure
• Previous evidence of hypersensitivity to sotalol
• Serum potassium <4 mEq/L
• For the treatment of AFIB/AFL, SOTALAR is also contraindicated in patients with:
  • Baseline QT interval >450 ms
  • Creatinine clearance < 40 mL/min

Warnings and Precautions

Drug Interactions

Antiarrhythmics and other QT Prolonging Drugs: Discontinue Class I or Class III anti-arrhythmic agents for at least three half-lives prior to dosing with SOTALAR. Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other class III antiarrhythmic drugs (e.g. amiodarone) are not recommended as concomitant therapy with SOTALAR, because of their potential to prolong refractoriness. 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 SOTALAR. SOTALAR should be administered with caution in conjunction with other drugs known to prolong the QT interval such as phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics

Digoxin: Single and multiple doses of SOTALAR 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: SOTALAR 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. Monitor such patients for evidence of bradycardia and 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 SOTALAR 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: Patients in need of beta-agonists should not normally receive SOTALAR. However if concomitant therapy is necessary, beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages with SOTALAR.

Clonidine: Concomitant use with sotalol increases the risk of bradycardia. Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving SOTALAR. Withdraw SOTALAR several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

Antacids: Administration of SOTALAR within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it may result in a reduction in Cmax 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 SOTALAR has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

Potassium-Depleting Diuretics: Hypokalemia or hypomagnesaemia may occur, increasing the potential for torsade de pointes.

Other Potassium-Depleting Drugs: Amphotericin B (IV route), corticosteroids (systemic administration), and some laxatives may also be associated with hypokalemia; potassium levels should be monitored and corrected appropriately during concomitant administration with SOTALAR.

Neuromuscular Blocking Agents like Tubocurarin: The neuromuscular blockade is prolonged by beta-blocking agents

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.

QT Prolongation and Proarrhythmia

SOTALAR can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. Factors such as reduced creatinine clearance, female sex, higher doses, reduced heart rate and history of sustained VT/VF or heart failure increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval (see DOSAGE AND ADMINISTRATION).

Correct hypokalemia or hypomagnesemia prior to initiating SOTALAR, as these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs. Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment (see DOSAGE AND ADMINISTRATION).

In general, do not use sotalol with other drugs known to cause QT prolongation (see Drug Interactions)

Bradycardia/Heart Block/Sick Sinus Syndrome

Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of

patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.

SOTALAR is contraindicated in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pauses or sinus arrest.

Hypotension

Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension. Monitor hemodynamics in patients with marginal cardiac compensation.

Heart Failure

New onset or worsening heart failure may occur during initiation or uptitration of sotalol because of its beta-blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur. Caution is advised when initiating therapy in patients with left ventricular dysfunction controlled by therapy (i.e. ACE Inhibitors, diuretics, digitalis, etc.); a low initial dose and careful dose titration is appropriate.

Electrolyte Disturbances

SOTALAR should not be used in patients with hypokalemia or hypomagnesaemia prior to correction of imbalance; these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsades de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant magnesium- and/or potassium-depleting drugs.

Recent MI

In post-infarction patients with impaired left ventricular function, the risk versus benefit of sotalol administration must be considered. Careful monitoring and dose titration are critical during initiation and follow-up of therapy. SOTALAR should be avoided in patients with left ventricular ejection fractions <40% without serious ventricular arrhythmias.

Cardiac Ischemia after Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Following abrupt cessation of therapy with beta adrenergic blockers, exacerbation of angina pectoris, arrhythmias, and in some cases, myocardial infarction may occur. Patients should be carefully monitored when discontinuing chronically administered SOTALAR, particularly those with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks, if possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat appropriately (consider use of an alternative beta blocker). Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease may be common, but unrecognized, in patients treated with sotalol, abrupt discontinuation may unmask latent coronary insufficiency. and consider the temporary use of an alternate beta-blocker if appropriate. If possible the dosage of SOTALAR should be gradually reduced over a period of one to two weeks. If angina or acute coronary insufficiency develops, appropriate therapy should be instituted promptly. Abrupt discontinuation may unmask latent coronary insufficiency. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. In addition, hypertension may develop.

Bronchospasm

Patients with bronchospastic diseases (for example chronic bronchitis and emphysema) should in general not receive beta-blockers. It is prudent, if SOTALAR is to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors may be minimized.

Anaphylaxis

Patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge while taking beta-blockers, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reaction.

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

As with other beta-blocking agents, Sotalol 40mg Tablets should be used with caution in patients undergoing surgery and in association with anesthetics that cause myocardial depression, such as cyclopropane or trichloroethylene.

Masked Signs of Hypoglycemia in Diabetes Mellitus

SOTALAR should be used with caution in patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycaemia, since beta-blockade may mask some important signs of the onset of acute hypoglycaemia, e.g. tachycardia.

Thyrotoxicosis

Beta-blockade may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.

Renal Impairment

Because sotalol is excreted mainly in urine, the dosage should be reduced when the creatinine clearance is less than 60 ml/min (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment

No dosage adjustment is required in patients with hepatic impairment.

Pregnancy

Pregnancy Category B

Although there are no adequate and well-controlled studies in pregnant women, sotalol 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, SOTALAR should be used during pregnancy only if the potential benefit outweighs the potential risk.

Lactation

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from sotalol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old. SOTALAR is not intended for administration in children.

Geriatric Use

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. 

Effects on Ability to Drive and use Machines

There are no data available, but the occasional occurrence of side effects such as dizziness and fatigue should be taken into account (see UNDESIRABLE EFFECTS)

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions 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 and are dose related.

Ventricular Arrhythmias

Serious Adverse Reactions

In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT

was about 0.7%. Incidence of Torsade de Pointes arrhythmias in patients with VT/VF are shown in Table 3.

* Highest on-therapy value

† Number of patients assessed

Table 4 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline in patients with ventricular arrhythmias. It should be noted, however, that the highest on-therapy QTc 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 QTc.

( ) Number of patients assessed

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%. Incidence of discontinuation for these adverse reactions was dose related.

One case of peripheral neuropathy that resolved on discontinuation of sotalol and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study.

Atrial Fibrillation/Atrial Flutter

Placebo-controlled Clinical Trials

In a pooled clinical trial population consisting of 4 placebo-controlled studies with 275 patients with atrial fibrillation (AFIB)/atrial flutter (AFL) treated with 160 to 320 mg doses of sotalol the following adverse reactions presented in Table 4 occurred in at least 2% of placebo-treated patients and at a lesser rate than sotalol treated patients. The data are presented by incidence of reactions in the sotalol and placebo groups by body system and daily dose.

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 reactions leading to discontinuation of sotalol were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

The following adverse events considered related to therapy, also occurred in 1% or more of patients treated with sotalol.

Cardiovascular: Edema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope.

Gastro-intestinal: Flatulence

Dermatologic: Rash

Musculoskeletal: Cramps

Nervous/psychiatric: Sleep disturbances, perspiration, depression, paresthesia, anxiety, mood changes

Urogenital: Sexual dysfunction

Special Senses: Visual disturbances, taste abnormalities, hearing disturbances

Body as a Whole: Infection, fever, localized pain

Cold and cyanotic extremities, Raynaud's phenomenon, increase in existing intermittent claudication and dry eyes have been seen in association with other beta-blockers.

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval use of sotalol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Voluntary reports since introduction include reports (less than one report per 10,000 patients) of: emotional lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Intentional or accidental overdosage with sotalol has rarely resulted in death. Hemodialysis has a large reduction of plasma levels of sotalol.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycaemia. In cases of massive intentional overdosage (2-16 g) of sotalol, the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT-interval, Torsades de Pointes, ventricular tachycardia and premature ventricular complexes.

If overdosage occurs, therapy with SOTALAR should be discontinued and the patient observed closely.

Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia Or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block (second and third degree): Transvenous cardiac pacing.

Hypotension: Adrenaline rather than isoproterenol or noradrenaline may be useful, depending on associated factors.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant.

Torsades de pointes: DC cardioversion, transvenous cardiac pacing, adrenaline, magnesium sulphate.

Incompatibility

Not Applicable

Shelf-Life

2 years

Storage and Handling Instructions

Store in a cool place. Protect from light.

Packaging Information

SOTALAR 40: Strip of 10 tablets

Last Updated: August 2018

Last Reviewed: August 2018