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Logo SOTACOR TABLETS 80 mg
SOTACOR TABLETS 160 mg
SOTACOR INJECTION 40 mg/4 mL
SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

SOTACOR TABLETS 80 mg
SOTACOR TABLETS 160 mg
SOTACOR INJECTION 40 mg/4 mL

COMPOSITION:
SOTACOR tablets 80 mg contain 80 mg of sotalol hydrochloride
SOTACOR tablets 160 mg contain 160 mg of sotalol hydrochloride
SOTACOR injection: Sterile solution containing 10 mg sotalol hydrochloride per mL.
SOTACOR (sotalol) is the hydrochloride of 4-(2-isopropylamino-1-hydroxyethyl)- methane sulphonanilide.

PHARMACOLOGICAL CLASSIFICATION:
A 5.2. Medicines affecting autonomic functions - adrenolytics (sympathicolytics).

PHARMACOLOGICAL ACTION:
SOTACOR (sotalol HCl) is a competitive nonselective beta-adrenergic receptor blocking agent, affecting both B1 and B2 receptors, devoid of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (MSA). SOTACOR inhibits renin release.
Its beta-adrenergic blocking 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.
SOTACOR has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties.
The Class II and III properties may be reflected on the surface electrocardiogram by a lengthening of the PR, QT and QTc (QT corrected for heart rate) intervals with no significant alteration in the QRS duration.
The d- and l- isomers of sotalol HCl have similar Class III antiarrhythmic effects while the l -isomer is responsible for virtually all of the beta-blocking activity.
Pharmacokinetics:
After oral administration, peak levels are reached in 2.5 to 4 hours, and steady-state plasma levels are attained within 2-3 days. The absorption is reduced by approximately 20% when administered with a standard meal, in comparison to fasting conditions.
SOTACOR displays dose proportionality with respect to plasma concentrations.
SOTACOR exhibits an extended half-life of 10-20 hours.
SOTACOR does not bind to plasma proteins and is not metabolised.
SOTACOR does not cross the blood-brain barrier in significant amounts.
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 faeces. Lower doses are necessary in conditions of renal impairment (see PRECAUTIONS). Age does not significantly alter the pharmacokinetics, although impaired renal function in geriatric patients can decrease the excretion rate, resulting in increased drug accumulation. Hepatic dysfunction has no effect on the pharmacokinetics of sotalol.
Haemodynamics:
Intravenous and oral SOTACOR produce consistent reductions in heart rate and cardiac output, with no reduction in stroke volume.
SOTACOR 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, SOTACOR produces significant reductions in both systolic and diastolic blood pressures. Although SOTACOR is usually well-tolerated haemodynamically, caution should be exercised in patients with marginal cardiac reserve as deterioration in cardiac performance may occur.
Electrophysiology:
In man, the Class II, (beta-blockade) electrophysiological effects of SOTACOR are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects 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. Occasionally prolongation in QRS interval may be observed.

INDICATIONS:
SOTACOR tablets are indicated in the management of:
  Hypertension:
Mild to moderate hypertension.
  Angina Pectoris:
SOTACOR reduces the incidence and severity of anginal attacks and increases effort tolerances.
  Dysrhythmias:
SOTACOR can be used in the prevention and treatment of the following dysrhythmias:
Paroxysmal supraventricular tachycardia;
Premature contractions (extra systoles) in atria or ventricles associated with ischaemic heart disease;
Life threatening or symptomatic ventricular tachyarrhythmias
Dysrhythmias due to excessive sympathetic stimulation.
SOTACOR intravenous is indicated in the treatment of the following arrhythmias:
  a) Paroxysmal Supraventricular Tachycardia
  b) Premature Contractions (Extra Systoles) in Atria or Ventricles
  c) Atrial Flutter and Atrial Fibrillation:
  d) Life threatening or symptomatic ventricular tachyarrhythmias.

CONTRA-INDICATIONS:
SOTACOR should be contra-indicated in patients with:
1. Cardiac decompensation, unless heart failure is treated at the same time.
2. Bronchial asthma and/or severe allergy and bronchitis.
3. Sinus bradycardia.
4. Cardiogenic shock.
5. Hypertensive crisis.
6. Sick sinus syndrome, second and third degree A-V block unless a functioning pacemaker is present.
7. Right ventricular failure secondary to pulmonary hypertension.
8. Anaesthesia that produces myocardial depression.
9. SOTACOR should never be given to patients with a phaeochromocytoma without concomitant alpha blockade.
10. Psychotropic drug treatment (including MAO inhibitors) which potentiate the action of beta-adrenergic blocking agents.
11. Should not be administered within several days of discontinuing cardiodepressant calcium channel blockers eg. Verapamil and diltiazem.
12. Chronic respiratory disease, peripheral vascular disease, Raynaud's disease, patients with prolonged fasting or those in a state of diabetic keto acidosis or metabolic acidocis.
13. Hypersensitivity to sotalol or to any ingredients of the formulation.
14. Renal impairment.
15. Congenital or acquired long QT syndrome.
  The dose must be reduced in the elderly.

WARNINGS:
Proarrhythmia
The most dangerous adverse effect of SOTACOR is the aggravation of preexisting arrhythmias or the provocation of new arrythmias. SOTACOR prolongs the QT interval and 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 in heart rate, reduction in serum potassium and magnesium (eg, as a consequence of diuretic use), high plasma drug concentrations (eg, as a consequence of overdosage or renal insufficiency), and with the concomitant use of sotalol and other medications such as antidepressants and Class I antiarrhythmics which have been associated with torsades de pointes. Females appear to be at increased risk of developing torsades de pointes. ECG monitoring immediately prior to or following the episodes usually reveals a significantly prolonged QT interval and a significantly prolonged QTc interval. In clinical trials, SOTACOR generally has not been initiated to patient whose pretreatment QTc interval exceeded 450 msec. SOTACOR should be titrated very cautiously in patients with prolonged QT intervals.
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 (eg, syncope), they can progress to ventricular fibrillation.
Percent incidence of serious proarrhythmias by dose for patients with sustained ventricular tachycardia/ventricular fibrillation.
DAILY DOSE (mg) INCIDENCE OF SERIOUS PROARRHYTHMIAS*
        1 –80         0
        81 –160         0,5%
        161 –320         1,8%
        321 –480         4,5%
        481 –640         4,5%
        > 640         6,8%
        *Torsades de Pointe or new sustained ventricular tachycardia/ventricular fibrillation.
Other risk factors for torsades de pointe were excessive prolongation of the QTc 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. Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment, events tend to occur within 7 days of initiating therapy or with an increase in dose. Initiating therapy at 80 mg BID with gradual upward dose titration thereafter reduces the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION). SOTACOR should be used with caution if the QTc is greater than 500 msec on-therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when the QT interval exceeds 550 msec. Due to the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QTc interval.
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 beta-blocker therapy. Therefore it is prudent when discontinuing chronically administered SOTACOR, particularly in patients with ischemic heart disease, to carefully monitor the patient. If possible, the dosage should be gradually reduced over a period of one to two weeks. Because coronary artery disease is common and may be unrecognized in patients receiving SOTACOR, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.
Congestive Heart Failure: Beta-blockade my 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. The adverse results of clinical trials involving antiarrhythmic drugs (i.e., apparent increase in mortality) suggest that SOTACOR should be avoided in patients with left ventricular ejection fractions <40% without serious ventricular arrhythmias.
Electrolyte Disturbances: SOTACOR should not be used in patients with hypokalemia or hypomagnesemia 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.
Electrocardiographic Changes: Excessive prolongation of the QT interval, >550 msec can be a sign of toxicity, and should be avoided. Sinus bradycardia (heart rate <50 bpm) occurred in arrhythmia patients receiving SOTACOR in clinical trials. Bradycardia itself increases the risk of torsades de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in a few patients 2nd or 3rd degree AV block also occur.
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 epinephrine used to treat the allergic reaction.

DOSAGE AND DIRECTIONS FOR USE:
Oral Indications
The optimal dosage varies from patient to patient and the dosage should be titrated to suit the individual patient.
Hypertension:
Initial dose 160 mg day.
Dosage may be increased by 80 mg per day at weekly intervals until blood pressure is controlled.
The dosage range is 160 mg - 320 mg once a day.
The individual optimal dosage should be determined from weekly blood pressure readings and pulse rates.
Note:
Dosage should be decreased or discontinued if the pulse rate falls below 50 beats/minute.
Following a reduction in blood pressure, the dosage should not be increased until the new blood pressure level is stable.
A reduction in dosage will alleviate symptoms of weakness and dizziness if blood pressure continues to fall after a month or two on a maintenance dose. SOTACOR may be used concomitantly with other antihypertensives (excluding clonidine).
Caution should be exercised when transferring a patients from clonidine. The withdrawal of clonidine may result in the release of large amounts of catecholamines which may give rise to a hypertensive crisis. If SOTACOR is administered in these circumstances, the unopposed alpha-receptor stimulation may aggravate this hypertension effect.
Combination with other potent antihypertensive drugs should not be used until the effects of SOTACOR alone have been determined.
Adrenergic inhibiting medicines (methyldopa, guanethidine) may produce side-effects while lowering blood pressure. In this instance, SOTACOR may be added to the antihypertensive regimen in progressively increasing doses while reducing the dose of the antihypertensive medicine below that which produced the side-effects. When the adrenergic inhibiting medicines are to be completely replaced by SOTACOR, their dosages should be gradually reduced while SOTACOR therapy is begun and its dosage is gradually increased.
Angina:
The recommended initial dose is 160 mg daily.
Dosage may be increased by 80 mg/day at weekly intervals until the optimal therapeutic effect is obtained. Dose range 160-320 mg/day.
Note:
The rapidity with which the dosage is increased depends upon the patient's tolerance, particularly as measured by the degree of induced bradycardia, (the heart rate at rest should not fall below 50 beats/minute), and the clinical response measured by the relief of the anginal attacks. Attacks of angina in a few patients may be adequately controlled at a daily dose of 160 mg/day (initial dosage). Other patients will need an increase in dosage up to recommended maximum of 320 mg/day. Generally no additional therapeutic benefit is derived by further increasing the dosage.
Dysrhythmia:
SOTACOR should be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualized for each patient on the basis of therapeutic response and tolerance. Proarrhythmic events can occur not only at initiation of therapy but also with each upward dosage adjustment.
Oral dosage should be adjusted gradually allowing 2-3 days between dosing increments in order to attain steady-state, and allow monitoring of QT intervals.
The recommended initial oral dosing schedule is 160 mg/daily given in two divided doses. The dose may be increased, if necessary, after appropriate evaluation to 240-320 mg/day. In most patients, a therapeutic response is obtained at a total daily dose of 160-320 mg/day, given in two divided doses. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480-640 mg/day; however these doses should only be prescribed when other treatment modalities have failed or are contra-indicated.
Note: Before starting SOTACOR therapy, previous antiarrhythmic agents should generally be withdrawn under careful monitoring for a minimum period of 2-4 drug half-lives, if the patient's clinical condition permits. After discontinuation of amiodarone, SOTACOR should not be initiated until the QTc interval is less than 450 msec (see WARNINGS).
Intravenous Indications:
SOTACOR usually slows atrio-ventricular conduction and reduces ventricular rate. Normal sinus rhythm may be restored in patients especially if the arrhythmia is of recent onset. In established cases, an increased amount of artrioventricular block will result with possible reversion to normal sinus rhythm.
Whilst a beta-adrenergic blocking agent is not the treatment of choice, SOTACOR may be used alone or in combination with other agents if DC cardioversion is not indicated, successful or practical. The patient should be monitored by constant electrocardiography for myocardial function.
Acute Arrhythmia:
Intravenous:
20 to 60 mg, administered intravenously over a 10 minute period. Can be repeated at 6 hourlyintervals if necessary.
Continuous electrocardiogram monitoring is recommended
Caution:
If excessive bradycardia (and/or hypotension) occurs, atropine 1,0 to 2,0 mg should be given intravenously, immediately followed if necessary, by a beta receptor stimulating agent, such as isoprenaline 5 micrograms/minute, intravenously up to 25 micrograms initially.

SIDE-EFFECTS AND SPECIAL PRECAUTION:
The most significant adverse events are those due to proarrhythmia, including torsades de pointes. (See WARNINGS).
Other adverse events include:
Cardiovascular: Bradycardia, dyspnoea, chest pain, palpitations, oedema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope.
Dermatologic: Rash.
Gastrointestinal: Nausea/vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, constipation.
Musculoskeletal: Cramps.
Nervous/Psychiatric: Fatigue, dizziness, asthenia, light-headedness, headache, sleep disturbances, depression, paresthesia, mood changes, anxiety, hallucinations.
Urogenital: Sexual dysfunction
Special senses: Visual disturbances, taste abnormalities, hearing disturbances.
Body as a Whole: Fever.
Vascular disease, peripheral vascular gangrene, Raynaud's disease, hypoglycaemia, skeletal muscle weakness, weight gain, dry mouth and cold extremities.
Precautions
Anesthesia:        Caution is advised with the use of beta-adrenoreceptor blocking agents including SOTACOR in patients undergoing surgery and in association with anesthetics that cause myocardial depression, such as cyclopropane, or trichloroethylene.
Diabetes Mellitus: In patients with diabetes mellitus (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia, SOTACOR should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia, e.g. tachycardia.
Thyrotoxicosis: Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. 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.
Hepatic Impairment: Since SOTACOR is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of SOTACOR.
Renal Impairment: SOTACOR is mainly eliminated 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 half-life of SOTACOR and urinary excretion.
Psoriasis: Beta-blocking drugs have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.
Beta-adrenergic receptor blocking agents should not be administered to patients with a resting pulse rate lower than 60 beats per minute.
Note:
Reduced dosages should be used in elderly patients, in patients with renal decompensation and in patients who receive the medicine intravenously, as adverse reactions are more common in such patients.
Particular caution should be exercised in administering SOTACOR to patients suffering from peripheral vascular disease and Raynaud's phenomenon.
Treatment with SOTACOR may be associated with exacerbation of peripheral vascular disease or with the development of Raynaud's phenomenon (due to unopposed arteriolar alpha-sympathetic activation).
In the peri-operative period it is generally unwise to reduce the dosage to which the patient is accustomed as there may be a danger of aggravation of angina pectoris or of hypertension during the surgical period. A patient's normal tachycardia response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard.
Interactions:
Antiarrhythmic: Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with SOTACOR, because of their potential to prolong refractoriness (see WARNINGS). The concomitant use of other beta-blocking agents with SOTACOR may result in additive Class II effects.
Potassium-Depleting Diuretics: Hypokalemia or hypomagnesemia may occur, increasing the potential for torsades de pointes (see WARNINGS, Electrolyte Disturbances).
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 Class I antiarrhythmic agents, phenothiazines, tricyclic antidepressants, terfenadine and astemizole and certain quinolone antibiotics (see WARNINGS).

Digoxin: Single and multiple doses of SOTACOR do not significantly affect serum digoxin levels. Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; however, this may be related to the presence of Congestive Heart Failure (CHF), a risk factor for proarrhythmia, in the patient receiving digoxin.
MAO Inhibitors: Potentiation of action of beta-blocker.
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 atrio-ventricular 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: Hyperglycaemia may occur, and the dosage of antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked by SOTACOR.
Beta-2-receptor stimulants: Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with SOTACOR (see CONTRAINDICATIONS)
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.
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 high performance liquid chromatographic assay with solid phase extraction.
Pregnancy:
The safety of SOTACOR in pregnancy has not been established.
SOTACOR has been shown to cross the placenta, and is found in amniotic fluid. Therefore, SOTACOR should be used during pregnancy only if the potential benefits outweigh the potential risk.
The administration of this class of medicine to pregnant mothers shortly before giving birth or during labour may result in the newborn infants being born hypotonic, collapsed and hypoglycaemic.
SOTACOR is excreted in breast milk.
Paediatric Use:
The safety and effectiveness of SOTACOR in children under 18 has not been established.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Intentional or accidental overdosage with SOTACOR has rarely resulted in death. Haemodialysis results in a large reduction of plasma levels of SOTACOR.
Symptoms and Treatment of Overdosage: The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2-16 grams) of SOTACOR the following clinical findings were seen: hypotension, bradycardia, prolongation of QT interval, premature ventricular complexes, ventricular tachycardia, torsades de pointes. If overdosage occurs, therapy with SOTACOR should be discontinued and the patient observed closely. In addition, 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): Transvenous cardiac pacing
Hypotension: Epinephrine rather than isoproterenol or norepinephrine may be useful, depending on associated factors.
Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant.
Torsades de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, and/or magnesium sulfate.

IDENTIFICATION:
SOTACOR Tablets 80 mg - light blue, biconvex capsule-shaped tablet. Plain on one side and engraved "BMS 621" with a breakbar on the other side.
SOTACOR Tablets 160 mg - light blue, biconvex capsule-shaped tablet. Plain on one side and engraved "BMS 160" and a bisect bar on the other side.
SOTACOR Injection 40 mg/4 mL clear, colourless liquid.

PRESENTATION:
SOTACOR Tablets 80 mg in plastic containers of 100.
SOTACOR Tablets 160 mg in plastic containers of 100.
SOTACOR Injection ampoules containing 40 mg/4 mL.

STORAGE CONDITIONS:
Store in dry place at room temperature not exceeding 25°C.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
SOTACOR Tablets 80 mg                F/5.2/170
SOTACOR Tablets 160 mg         H/5.2/48
SOTACOR Injection 40 mg/4 mL         J/5.2/282

NAME AND BUSINESS ADDRESS OF APPLICANT:
Bristol-Myers Squibb (Pty) Ltd *
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 2000

Authorised user of the TM SOTACOR.

Updated on this site: January 2003
Source: Pharmaceutical Industry

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