Non-cardioselective b-blockers (beta-blockers).

Sotalol

Sotacor tablets 80mg: Each tablet contains 80mg sotalol hydrochloride. Sotacor tablets 160mg: Each tablet contains 160mg sotalol hydrochloride.

Sotacor tablets 80mg: Tablets Round, biconvex, white tablets scored on one side and engraved on the other side with “80”. Sotacor tablets 160mg: Tablets Round, biconvex, white tablets scored on one side and engraved on the other side with “160

SOTACOR tablets are indicated for:

Ventricular arrhythmias:

- Treatment of life-threatening ventricular tachyarrhythmias;

- Treatment of 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

The initiation of treatment or changes in dosage with SOTACOR should follow an appropriate medical evaluation including ECG control with measurement of the corrected QT interval, and assessment of renal function, electrolyte balance, and concomitant medications.

As with other antiarrhythmic agents, it is recommended that SOTACOR be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualized and based on the patient's response. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

In view of its β-adrenergic blocking properties, treatment with SOTACOR should not be discontinued suddenly, especially in patients with ischaemic heart disease (angina pectoris, prior acute myocardial infarction) or hypertension, to prevent exacerbation of the disease.

The following dosing schedule can be recommended:

The initial dose is 80 mg, administered either singly or as two divided doses.

Oral dosage of SOTACOR should be adjusted gradually allowing 2-3 days between dosing increments in order to attain steady-state, and to allow monitoring of QT intervals. Most patients respond to a daily dose of 160 to 320 mg administered in two divided doses at approximately 12 hour intervals. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480 - 640 mg/day. These doses should be used under specialist supervision and should only be prescribed when the potential benefit outweighs the increased risk of adverse events, particularly proarrhythmias.

Children

SOTACOR is not intended for administration to children.

Dosage in renally impaired patients

Because SOTACOR is excreted mainly in urine, the dosage should be reduced when the creatinine clearance is less than 60 ml/min according to the following table:

The creatinine clearance can be estimated from serum creatinine by the Cockroft and Gault formula:

Men: (140 - age) × weight (kg)

72 × serum creatinine (mg/dl)

Women: idem × 0.85

When serum creatinine is given in µmol/l, divide the value by 88.4 (1mg/dl = 88.4 µmol/l).

Dosage in hepatically impaired patients

No dosage adjustment is required in hepatically impaired patients.

Not recommended.

SOTACOR should not be used where there is evidence of sick sinus syndrome; second and third degree AV heart block unless a functioning pacemaker is present; congenital or acquired long QT syndromes; torsades de pointes; symptomatic sinus bradycardia; uncontrolled congestive heart failure; cardiogenic shock; anaesthesia that produces myocardial depression; untreated phaeochromocytoma; hypotension (except due to arrhythmia); Raynaud's phenomenon and severe peripheral circulatory disturbances; history of chronic obstructive airway disease or bronchial asthma (a warning will appear on the label); hypersensitivity to any of the components of the formulation; metabolic acidosis; renal failure (creatinine clearance < 10 ml/min).

Abrupt Withdrawal Hypersensitivity to catecholamines is observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias, and in some cases, myocardial infarction have been reported after abrupt discontinuation of therapy. Patients should be carefully monitored when discontinuing chronically administered SOTACOR, particularly those with ischaemic heart disease. If possible the dosage should be gradually reduced over a period of one to two weeks, if necessary at the same time initiating replacement therapy. Abrupt discontinuation may unmask latent coronary insufficiency. In addition, hypertension may develop.

Proarrhythmia The most dangerous adverse effect of Class I and Class III antiarrhythmic drugs (such as sotalol) is the aggravation of pre-existing arrhythmias or the provocation of new arrhythmias. Drugs that prolong the QT-interval may cause torsades de pointes, a polymorphic ventricular tachycardia associated with prolongation of the QT-interval. Experience to date indicates that the risk of torsades de pointes is associated with the prolongation of the QT-interval, reduction of the heart rate, reduction in serum potassium and magnesium, high plasma sotalol concentrations and with the concomitant use of sotalol and other medications which have been associated with torsades de pointes (see § 4.5: Interactions). Females may be at increased risk of developing torsades de pointes.

The incidence of torsades de pointes is dose dependent. Torsades de pointes usually occurs within 7 days of initiating therapy or escalation of the dose and can progress to ventricular fibrillation.

In clinical trials of patients with sustained VT/VF the incidence of severe proarrhythmia (torsades de pointes or new sustained VT/VF) was <2% at doses up to 320 mg. The incidence more than doubled at higher doses.

Other risk factors for torsades de pointes were excessive prolongation of the QT_C and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure have the highest risk of serious proarrhythmia (7%).

Proarrhythmic events must be anticipated not only on initiating therapy but with every upward dose adjustment. Initiating therapy at 80 mg with gradual upward dose titration thereafter reduces the risk of proarrhythmia. In patients already receiving SOTACOR caution should be used if the QT_C exceeds 500msec whilst on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when the QT_C-interval 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.

Electrolyte Disturbances SOTACOR should not be used in patients with hypokalaemia 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 diarrhoea or patients receiving concomitant magnesium- and/or potassium-depleting drugs.

Congestive Heart Failure Beta-blockade may further depress myocardial contractility and precipitate more severe heart failure. 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.

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. SOTACOR should be avoided in patients with left ventricular ejection fractions <40% without serious ventricular arrhythmias.

Electrocardiographic Changes Excessive prolongation of the QT-interval,>500 msec, can be a sign of toxicity and should be avoided (see Proarrhythmias above). Sinus bradycardia has been observed very commonly in arrhythmia patients receiving sotalol in clinical trials. Bradycardia 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 2nd- or 3rd-degree AV block is approximately 1%.

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. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reaction.

Anaesthesia As with other beta-blocking agents, SOTACOR should be used with caution in patients undergoing surgery and in association with anaesthetics that cause myocardial depression, such as cyclopropane or trichloroethylene.

Diabetes Mellitus SOTACOR 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 As sotalol is mainly eliminated via the kidneys the dose should be adjusted in patients with renal impairment (see dosage).

Psoriasis Beta-blocking drugs have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.

AntiarrhythmicsClass 1a antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other antiarrhythmic drugs such as amiodarone and bepridil are not recommended as concomitant therapy with SOTACOR, because of their potential to prolong refractoriness. The concomitant use of other beta-blocking agents with SOTACOR may result in additive Class II effects.

Other drugs prolonging the QT-interval SOTACOR should be given with extreme caution in conjunction with other drugs known to prolong the QT-interval such as phenothiazines, tricyclic antidepressants, terfenadine and astemizole. Other drugs that have been associated with an increased risk for torsades de pointes include erythromycin IV, halofantrine, pentamidine, and quinolone antibiotics.

Floctafenine beta-adrenergic blocking agents may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by Floctafenine.

Calcium channel 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 on atrioventricular conduction, and ventricular function.

Potassium-Depleting Diuretic : Hypokalaemia 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 hypokalaemia; potassium levels should be monitored and corrected appropriately during concomitant administration with SOTACOR.

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.

Digitalis glycosides Single and multiple doses of SOTACOR do not significantly affect serum digoxin levels. Proarrhythmic events were more common in sotalol treated patients also receiving digitalis glycosides; however, this may be related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digitalis glycosides. Association of digitalis glycosides with beta-blockers may increase auriculo-ventricular conduction time.

Catecholamine-depleting agents Concomitant use of catecholamine-depleting drugs, such as reserpine, guanethidine, or alpha methyldopa, 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 hypoglycaemics Hyperglycaemia may occur, and the dosage of antidiabetic drugs may require adjustment. Symptoms of hypoglycaemia (tachycardia) may be masked by beta-blocking agents.

Neuromuscular blocking agents like Tubocurarin The neuromuscular blockade is prolonged by beta-blocking agents.

Beta-2-receptor stimulants Patients in need of beta-agonists should not normally receive SOTACOR. However, if concomitant therapy is necessary beta-agonists may have to be administered in increased dosages .

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 phaeochromocytoma and who are treated with sotalol should have their urine screened utilizing the HPLC assay with solid phase extraction

The most frequent adverse effects of sotalol arise from its beta-blockade properties. Adverse effects are usually transient in nature and rarely necessitate interruption of, or withdrawal from treatment. If they do occur, they usually disappear when the dosage is reduced. The most significant adverse effects, however, are those due to proarrhythmia, including torsades de pointes (See Warnings).

The following are adverse events considered related to therapy, occurring in 1% or more of patients treated with SOTACOR.

Cardiovascular Bradycardia, dyspnoea, chest pain, palpitations, oedema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope.

Dermatologic Rash.

Gastro-intestinal Nausea/vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence.

Musculoskeletal Cramps.

Nervous/psychiatric Fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paraesthesia, mood changes, anxiety.

Urogenital Sexual dysfunction.

Special Senses Visual disturbances, taste abnormalities, hearing disturbances.

Body as a whole Fever.

In trials of patients with cardiac arrhythmia, the most common adverse events leading to discontinuation of SOTACOR were fatigue 4%, bradycardia ( <50 bpm) 3%, dyspnoea 3%, proarrhythmia 2%, asthenia 2%, and dizziness 2%.

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

Bristol-Myers Pharmaceuticals

(POM)

26 June 2009