Sotacor (Sotalol HCl)

SOTACOR®

Bristol

Sotalol HCl

Antiarrhythmic

Action and Clinical

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol 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. Sotalol is noncardioselective and is not associated with partial agonist or membrane stabilizing activity. Like other beta-blockers, sotalol inhibits renin release. The renin-suppressive effect of sotalol is significant both at rest and during exercise. Its beta-adrenergic activity causes a reduction in heart rate (negative chronotropic effect) and a limited reduction in the force of contraction (negative inotropic effect). These cardiac changes reduce myocardial oxygen consumption and cardiac work. The class II and III properties may be reflected on the surface electrocardiogram by a lengthening of the PR, QT and Qt c (QT corrected for heart rate) intervals with no significant alteration in the QRS duration. Whereas significant beta-blockade may occur at oral doses as low as 25 mg, Class III effects are seen at daily doses of 160 mg and above. The antiarrhythmic activity of sotalol appears to be primarily due to the drug’s Class III property, based on animal models.

Pharmacologically, in addition to its antiarrhythmic properties, sotalol also has antihypertensive and anti-anginal properties.

Electrophysiology: Sotalol prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular and 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 atrioventricular 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 Qt c (see Warnings). 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 to 15 J) compared to a mean of 16 J for a nonrandomized comparative group primarily receiving amiodarone.

In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression versus 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 versus 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 versus 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 2-year mortality (13% versus 22%), the lowest 2-year VT recurrence rate (30% versus 60%), and the lowest withdrawal rate (38% versus about 75 to 80%). The most commonly used doses of sotalol in this trial were 320 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 versus no pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

Hemodynamics: In a study of systemic hemodynamic function measured invasively in 12 patients with a mean left ventricular (LV) ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 nonsustained), 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 postdosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant 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.

Sotalol causes little or no change in systemic blood pressure in normotensive patients, and no significant changes in pulmonary vascular pressures have been noted. 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).

Pharmacokinetics: 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. Over the dosage range of 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 10 to 20 hours.

Sotalol does not bind to plasma proteins and is not metabolized. The pharmacokinetics of the d and l enantiomers of sotalol are essentially identical. Sotalol crosses the blood brain barrier poorly. In one study, mean cerebrospinal fluid concentrations following a single oral dose ranged from 5 to 28% of those observed in plasma. The primary route of elimination is renal excretion. Approximately 80 to 90% of a dose is excreted unchanged in the urine, while the remainder is excreted in the feces.

Renally Impaired Patients: Lower doses are necessary in renal impairment (see Dosage and Precautions).

Hepatically Impaired Patients: Since sotalol is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of sotalol.

Geriatrics: Age does not significantly alter the pharmacokinetics of sotalol, but impaired renal function in elderly patients can increase the terminal elimination half-life, resulting in increased drug accumulation.

Effect of Food: When sotalol was administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to that in the fasting state.

Indications And Clinical Uses:

No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.

For the treatment of documented life-threatening ventricular arrhythmias such as sustained ventricular tachycardia. Sotalol may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of sotalol, its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.

For patients with sustained ventricular tachycardia, sotalol therapy should be initiated in the hospital. Hospitalization may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.

In view of the proarrhythmic effects of sotalol, its use in patients with hypertension or angina pectoris is not recommended unless they also require sotalol for the treatment of ventricular arrhythmias.

Contra-Indications:

In patients with bronchial asthma or chronic obstructive airway disease, allergic rhinitis, severe sinus node dysfunction, symptomatic sinus bradycardia, sick sinus syndrome, second- and third-degree AV block (unless a functioning pacemaker is present), congenital or acquired long QT syndrome, cardiogenic shock, severe or uncontrolled congestive heart failure, hypokalemia, renal failure, anesthesia with agents that produce myocardial depression and previous evidence of hypersensitivity to sotalol.

Warnings in Clinical States:

Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group. The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.

Proarrhythmia: Sotalol may cause new or worsen existing arrhythmias. Such proarrhythmic effects range from an increase in frequency of premature ventricular contractions to the development of more severe ventricular tachycardia, ventricular fibrillation or torsades de pointes. It is therefore essential that each patient administered sotalol be evaluated clinically and electrocardiographically prior to, and during therapy to determine whether the response to sotalol supports continued treatment. Sotalol, like some antiarrhythmic agents, has been associated with a specific form of arrhythmia, torsades de pointes, which is defined as a polymorphic ventricular tachycardia with prolongation of the QT interval and QRS complexes of changing amplitude that appear to twist around the isoelectric axis. Torsades have been observed more frequently in patients with an elevated baseline QT (>430 msec), on-therapy QT of >500 msec, bradycardia (heart rate <50 bpm), hypokalemia and hypomagnesemia (e.g., as a consequence of diuretic use) (see Warnings, Electrolyte Disturbances), high plasma drug concentrations (e.g., as a consequence of overdosage or renal insufficiency), with the concomitant use of sotalol and other medications such as antidepressants and Class I antiarrhythmics and congestive heart failure. ECG monitoring immediately prior to or following the episodes usually reveals a significantly prolonged QT interval and a significantly prolonged Qt c interval. In clinical trials, sotalol generally has not been initiated to patients whose pretreatment Qt c interval exceeded 450 msec. Sotalol should be titrated very cautiously in patients with prolonged QT intervals. Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and lack of efficacy. Thus, the incidence of drug-related events cannot be precisely determined and the rates of occurrence provided below must be considered approximations. It should be noted that drug-induced arrhythmias may often not be identified until late after starting the drug because of infrequent monitoring. Due to the possibility of proarrhythmic effects, sotalol is not recommended for the treatment of patients with asymptomatic premature contractions (see Indications).

Torsades de pointes is dose dependent, usually occurs early after initiating therapy or escalation of the dose, and terminates spontaneously in the majority of patients. Although most episodes of torsades de pointes are self-limited or associated with symptoms (e.g., syncope), they can progress to ventricular fibrillation.

Overall in clinical trials with sotalol, 4.3% of 3 257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, new or worsened sustained ventricular tachycardia was reported in approximately 1% of patients, and torsades de pointes in 2.4%. 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. In patients with a history of sustained ventricular tachycardia, the incidence of torsades de pointes was 4%, and worsened VT was approximately 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of torsades de pointes was 1% and 1.4%, respectively.

In addition to dose and presence of sustained VT, other risk factors for torsades de pointes were gender (females had a higher incidence), excessive prolongation of the QT c interval (see Table II) 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 patients experiencing torsades 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 Overdose: Symptoms and Treatment). It is not possible to determine whether some sudden deaths represented episodes of torsades de pointes, but in some instances sudden death did follow a documented episode of torsades de pointes. Although sotalol therapy was discontinued in most patients experiencing torsades de pointes, 17% were continued on a lower dose. Nonetheless, sotalol should be used with particular caution if the QT c is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QT c exceeds 550 msec. Due to the multiple risk-factors associated with torsades de pointes, however, caution should be exercised regardless of the QT c interval.

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (torsades de pointes and worsened VT) occurred within 7 days of initiating sotalol therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg b.i.d. with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of sotalol in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see Dosage).

Electrolyte Disturbances: Sotalol should not be used in patients with hypokalemia or hypomagnesemia prior to correction of such imbalance, as these conditions can exaggerate the degree of QT prolongation and increase the potential for torsades de pointes. The serum electrolytes must be monitored regularly and more frequently if diuretics are used concomitantly. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretics.

Congestive Heart Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure (CHF), and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Moreover, patients with CHF have a higher risk of torsades de pointes (see Warnings, Proarrhythmia).

In patients with controlled CHF, sotalol should be administered cautiously. The positive inotropic action of digitalis may be reduced when the 2 drugs are used concomitantly. Both digitalis and sotalol slow AV conduction. If cardiac failure continues despite adequate digitalization, sotalol should be discontinued. Caution is also advised when initiating therapy in patients with agents such as ACE inhibitors, diuretics etc.; a low initial dose and careful titration dose titration is appropriate.

In patients without a history of heart failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. At the first sign of impending heart failure, appropriate therapy must be established and consideration should be given to discontinuation of treatment with sotalol.

In clinical trials, new or worsened congestive heart failure (CHF) occurred in 3.3% (n=3 257) of patients and led to discontinuation in approximately 1% of patients receiving sotalol. The incidence was higher in patients presenting with sustained ventricular tachycardia/fibrillation (4.6%, n=1 363), or a prior history of heart failure (7.3%, n=696). Based on a life-table analysis, the one-year incidence of new or worsened CHF was 3% in patients without a prior history and 10% in patients with a prior history of CHF. NYHA Classification was also closely associated to the incidence of new or worsened heart failure in patients receiving sotalol (1.8% in 1 395 Class I patients, 4.9% in 1 254 Class II patients and 6.1% in 278 Class III or IV patients).

Conduction Disturbances: Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be avoided (see Proarrhythmia). 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 torsades de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of second- or third-degree AV block is approximately 1%.

Recent Myocardial Infarction: Caution should be exercised when sotalol is given to patients with recent myocardial infarction. Experience in the use of sotalol in the early stage of recovery from acute myocardial infarction is limited and, at least at high initial doses, not reassuring. In 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 therapy.

The adverse results of clinical trials involving antiarrhythmic drugs (i.e., apparent increase in mortality) suggest that sotalol should be avoided in patients with left ventricular ejection fractions £ 40% without serious ventricular arrhythmias.

In a large controlled trial in patients with a recent myocardial infarction without heart failure, who did not necessarily have ventricular arrhythmias, oral sotalol treatment was associated with a nonstatistically significant risk reduction in mortality compared to the placebo group (18%). In this post-infarction study using a fixed dose of 320 mg once daily and in a second small randomized trial in high-risk postinfarction patients with left ventricular ejection fractions £ 40% treated with high doses (640 mg/day), there were suggestions of an excess of early sudden deaths.

In a double-blind, placebo-controlled secondary prevention trial in 1 456 postinfarction patients who did not necessarily have ventricular arrhythmias, sotalol was given as a non-titrated dose of 320 mg once daily. The results did not suggest an adverse effect on survival; however, there was a suggestion of excess mortality (3% on sotalol versus 2% on placebo) during the first 10 days of the trial. In another trial, where high doses of sotalol (320 mg twice daily) were given to a small number of high-risk postinfarction patients (n=17 randomized to sotalol), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within 2 weeks of initiating sotalol.

Abrupt Cessation of Therapy: Patients should be warned against abrupt interruption or discontinuation of sotalol. Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. There have been occasional reports of severe exacerbation of angina pectoris, ventricular arrhythmias and in some cases myocardial infarction following abrupt discontinuation of beta-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, it is prudent when discontinuing chronically administered sotalol, particularly in patients with ischemic heart disease, to carefully monitor the patient and to discontinue sotalol in a stepwise manner or consider the temporary use of an alternate beta-blocker if appropriate. If possible, the dosage should be gradually reduced over a period of 1 to 2 weeks. The same frequency of administration should be maintained. If angina markedly worsens or acute coronary insufficiency develops, appropriate therapy should be instituted promptly. Because coronary artery disease is common and may be unrecognized in patients receiving sotalol, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.

Anaphylaxis: While taking beta-blockers, patients with a history of anaphylactic reactions to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic.

There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other hand, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.

Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema): Patients with bronchospastic diseases should in general not receive beta-blockers. It is prudent, if sotalol 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.

Skin Rashes and Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including sotalol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic-blocking agent (practolol). This syndrome has not been observed with sotalol. Physicians, however, should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.

Thyrotoxicosis: In patients with thyrotoxicosis, sotalol may mask the clinical signs of hyperthyroidism or its complications and give a false impression of improvement. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of sotalol which might be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

Precautions:

Renal Impairment: Renal function tests should be carried out at appropriate intervals. Caution should be observed in patients with impaired renal function since sotalol is eliminated mainly 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 and its urinary excretion. Guidance for dosing in conditions of renal impairment can be found under Dosage.

Diabetes: Sotalol should be administered with caution to patients with history of spontaneous hypoglycemia or to patients with diabetes (especially labile diabetes) receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia; e.g., tachycardia.

Anesthesia: It is not advisable to withdraw beta-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using sotalol with anesthetic agents such as cyclopropane or trichloroethylene which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg i.v.).

Some patients receiving beta-adrenoceptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting the heart and maintaining the heartbeat has also been reported.

In emergency surgery, since sotalol is a competitive antagonist at beta-adrenoceptor sites, its effects may be reversed, if required, by sufficient doses of such agonists as isoproterenol or epinephrine.

Pregnancy: There are no 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, sotalol should be used during pregnancy only if the potential benefit outweighs the potential risk.

Lactation: Sotalol has been reported to be present in human milk. Because of the potential for adverse reactions from sotalol in nursing infants, 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.

Children: The safety and effectiveness of sotalol in children under 18 have not been established.

Drug Interactions:

Antiarrhythmics: Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide, and Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with sotalol because of their potential to prolong refractoriness (see Warnings). 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 sotalol.

Potassium-Depleting Diuretics: Hypokalemia or hypomagnesia may occur, increasing the potential for torsades de pointes (see Warnings, Electrolyte Disturbances).

Drugs Prolonging the QT Interval: Sotalol should also be given with extreme caution in conjunction with other drugs known to prolong the QT interval, such as Class I and Class III antiarrhythmics, phenothiazines, tricyclic antidepressants, terfenadine, astemizole, erythromycin, lithium and liquid protein diets.

Digoxin: Single and multiple doses of sotalol do not significantly 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.

Calcium blocking drugs: Concurrent administration of beta-blocking agents and calcium channel blockers has resulted in hypotension, bradycardia, conduction defects, and cardiac failure. Beta-blockers should be avoided in combination with cardiodepressant calcium-channel blockers such as verapamil and diltiazem because of the additive effects of atrioventricular conduction and ventricular function.

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 should be closely monitored for evidence of hypotension and/or marked bradycardia, which may produce syncope.

Insulin and Oral Hypoglycemics: Hyperglycemia may occur and the dosage of antidiabetic drug may require adjustment. Symptoms of hypoglycemia may be masked by sotalol (see Precautions, Diabetes).

Clonidine: Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, the beta-blocker should be discontinued slowly several days before the gradual withdrawal of clonidine.

Beta-2-receptor Stimulants: Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol.

Drug/Laboratory Interaction: The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by photometric methods. Patients suspected of having pheochromocytoma and who are treated with sotalol should have their urine screened utilizing the high performance liquid chromatographic assay with solid phase extraction.

Adverse Reactions:

Sotalol is well tolerated in the majority of patients, with the most frequent adverse events arising from its beta-blockade properties. Adverse events are usually transient in nature and rarely necessitate interruption of, or withdrawal from treatment. These include dyspnea, fatigue, dizziness, headache, fever, excessive bradycardia and/or hypotension. If they do occur, these side effects usually disappear when the dosage is reduced. The most significant adverse events, however, are those due to proarrhythmia, including torsades de pointes.

During premarketing trials, 3 186 patients with cardiac arrhythmias (1 363 with sustained ventricular tachycardia) received oral sotalol, of whom 2 451 received the drug for at least 2 weeks. The most important adverse effects are torsades de pointes and other serious new ventricular arrhythmias (see Warnings), occurring at rates of almost 4% and 1%, respectively, in the VT/VF population. Overall, discontinuation because of unacceptable side effects was necessary in 18% of all patients in clinical trials, and in 13% of patients treated for at least 2 weeks. The most common adverse reactions leading to discontinuation of sotalol are as follows: fatigue 4%, bradycardia (<50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%.

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.

Potential Adverse Effects: Marketing experience with sotalol shows an adverse experience profile similar to that described above from clinical trials. Voluntary reports since introduction include rare 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, reversible alopecia.

Additional adverse effects have been reported with other beta-adrenergic blocking agents.

CNS: reversible mental depression progressing to catatonia; and acute reversible syndrome characterized by disorientation for time and place, short-term memory loss and decreased performance on neuropsychometrics.

Allergic: fever, combined with aching and sore throat, laryngospasm; respiratory distress.

Hematologic: agranulocytosis; thrombocytopenic or nonthrombocytopenia purpura.

Gastrointestinal: mesenteric arterial thrombosis; ischemic colitis.

Other: Peyronie’s disease, Raynaud’s phenomenon.

Symptoms And Treatment Of Overdose:

OverdoseIntentional or accidental overdosage with sotalol has rarely resulted in death.

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 g) with sotalol the following clinical findings were seen: hypotension, bradycardia, prolongation of QT interval, torsades de pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued. Close monitoring of the electrocardiogram in patients with suspected sotalol intoxication is essential. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QTc intervals are normalized.

Every effort should be made to correct promptly metabolic and electrolyte imbalances which might contribute to the initiation of ventricular arrhythmias (see Warnings).

If required, the following therapeutic measures are suggested: Bradycardia: atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block (second- and third-degree): isoproterenol or transvenous cardiac pacemaker.

Congestive Heart Failure: conventional therapy.

Hypotension: Epinephrine rather than isoproterenol or norepinephrine may be useful, depending on associated factors, in addition to atropine and digitalis (see Precautions).

Bronchospasm: aerosolized beta-2-receptor stimulant or aminophylline.

Hypoglycemia: i.v glucose.

Torsades de pointes: epinephrine and/or magnesium sulfate, transvenous cardiac pacing, DC cardioversion.

It should be remembered that sotalol is a competitive antagonist of isoproterenol and, hence, large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of sotalol. However, the complications of excess isoproterenol should not be overlooked.

Dosage And Administration:

Sotalol, when used for the treatment of documented life-threatening ventricular arrhythmias, should be initiated and dose increased in a hospital with facilities for cardiac rhythm monitoring and assessment (see Indications). Sotalol should be administered only after appropriate clinical assessment, and the dosage of sotalol must be individualized on the basis of therapeutic response and tolerance. The usefulness of monitoring plasma level for optimization of therapy has not been established. Proarrhythmic events can occur not only at the initiation of therapy, but also with each upward dosage adjustment.

Dosage of sotalol should be adjusted gradually, allowing 2 to 3 days between dosing increments in order to attain steady-state plasma concentrations and to allow monitoring of QT intervals. Graded dose adjustment will help prevent the use of doses which are higher than necessary to control the arrhythmia. The recommended initial dose is 160 mg daily, given in 2 divided doses at approximately 12-hour intervals and taken preferably 1 to 2 hours before meals. If needed, this dose may be increased, after appropriate evaluation, to 240 or 320 mg/day. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in 2 divided doses. Some patients with life-threatening refractory arrhythmias may require doses as high as 480 to 640 mg/day; however, these doses should only be prescribed when the potential benefit outweighs the increased risk of adverse events, in particular proarrhythmias. Because of the long elimination half-life of sotalol, dosing on more than a twice daily regimen is not usually necessary.

Patients experiencing bradycardia or hypotension on initial administration of sotalol should be removed from therapy; sotalol may be later reintroduced at a lower dose. A dose reduction may also be advisable to alleviate symptoms of weakness and dizziness in cases where blood pressure remains low after more than a month of therapy.

Renal Impairment: Because sotalol is excreted predominantly in urine and its terminal elimination half-life is prolonged in conditions of renal impairment, a longer duration of dosing is required to reach steady-state.

Transfer to and from Sotalol: Based on theoretical considerations rather than experimental data, the following suggestion is made: under careful monitoring and if the patient’s clinical condition permits, when transferring patients from another antiarrhythmic drug to sotalol or from sotalol to another antiarrhythmic agent, allow at least 3 to 4 half-lives to elapse for the drug being discontinued before starting the alternative drug at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient. After discontinuation of amiodarone, sotalol should not be initiated until the Qtc interval is less than 450 msec (see Warnings). Treatment has been initiated in some patients receiving i.v. lidocaine without ill effect.

Availability And Storage:

80 mg: Each light blue, biconvex, capsule-shaped tablet, engraved with SOTACOR on one side and a full bisect bar, BL and 80 on the other contains: sotalol HCl 80 mg. Nonmedicinal ingredients: colloidal silicon dioxide, FD&C Blue No. 2 aluminum lake, lactose, magnesium stearate, microcrystalline cellulose, starch and stearic acid. Bottles of 100.

160 mg: Each light blue, biconvex, capsule-shaped tablet, engraved with SOTACOR on one side and a full bisect bar, BL and 160 on the other contains: sotalol HCl 160 mg. Nonmedicinal ingredients: colloidal silicon dioxide, FD&C Blue No. 2 aluminum lake, lactose, magnesium stearate, microcrystalline cellulose, starch and stearic acid. Bottles of 100.

Store at room temperature (15 to 30°C).

SOTACOR® Bristol Sotalol HCl Antiarrhythmic

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