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APO-SOTALOL 80mg tablets are blue, capsule-shaped, biconvex tablets identified with "APO-80" on one side and scored on the other. Each tablet contains 80mg sotalol hydrochloride and typically weighs 137.5mg
APO-SOTALOL 160mg tablets are blue, capsule-shaped, biconvex tablets identified with "APO-160" on one side and scored on the other. Each tablet contains 160mg sotalol hydrochloride and typically weighs 275mg
Sotalol hydrochloride has both beta-adrenoreceptor blocking (Class II) and cardiac action potential duration prolongation (Class III) anti-arrhythmic 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 a nonselective beta-adrenergic blocking agent affecting both β1 and β2 adrenergic receptors devoid of intrinsic sympathomimetic activity (ISA) and membrane stabilising activity (MSA). At β1 adrenergic receptor sites - located chiefly in cardiac muscle - sotalol hydrochloride inhibits the chronotropic and inotropic responses of the heart; in the bronchial and vascular musculature, it occupies β2 adrenergic receptor sites, thus inhibiting bronchodilation and vasodilation. Like most other beta-adrenergic blockers, sotalol hydrochloride inhibits renin release. The renin-suppressive effect of sotalol hydrochloride is significant both at rest and during exercise. 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.
Sotalol hydrochloride uniformly prolongs the action potential duration in cardiac tissues by delaying only the repolarisation phase. Its major effects are prolongation of the atrial, ventricular and accessory pathway effective refractory periods. The Class II and Class 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 of the QRS duration.
Although significant beta-adrenergic blockade may occur at oral doses as low as 25mg, Class III effects are usually seen at daily doses of greater than 160mg.
Pharmacologically, in addition to its antiarrhythmic properties, sotalol hydrochloride also has antihypertensive and antianginal properties.
Haemodynamics: In humans, APO-SOTALOL produces consistent reductions in heart rate and cardiac output, with no reduction in stroke volume.
In hypertensive patients, APO-SOTALOL produces significant reductions in both systolic and diastolic blood pressures. Although sotalol hydrochloride is usually well tolerated haemodynamically, caution should be exercised in patients with marginal cardiac reserve as deterioration in cardiac performance may occur.
Electrophysiology: In humans, the Class II (beta-blockade) electrophysiological effects of sotalol hydrochloride 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 atrioventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160mg to 640 mg per day, the surface ECG shows dose-related mean increases of 40-100msec in QT and 10-40msec in QTc. No significant alteration in QRS interval is observed.
The bioavailability of oral sotalol hydrochloride 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. The absorption is reduced by approximately 20% when administered with a standard meal, in comparison to fasting conditions. Over the dosage range 40-640mg/day sotalol hydrochloride displays dose proportionality with respect to plasma concentrations. Distribution occurs to a central (plasma) and a peripheral compartment, with a mean elimination half-life of 10 to 20 hours.
Sotalol hydrochloride does not bind to plasma proteins and is not metabolised. The pharmacokinetics of the d- and l- enantiomers of sotalol hydrochloride are essentially identical. Sotalol hydrochloride crosses the blood-brain barrier poorly, with cerebrospinal fluid concentrations being 5%-28% of those observed in plasma. Sotalol is excreted by glomerular filtration and to a small extent by tubular secretion. 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 renally impaired patients.
APO-SOTALOL is indicated in the prevention and treatment of supraventricular and ventricular arrhythmias.
APO-SOTALOL should be taken 1-2 hours before meals.
Treatment with APO-SOTALOL should be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dose should be individualised for each patient on the basis of therapeutic response and tolerance. Proarrhythmic events can occur at initiation of therapy and with each upward dosage adjustment.
The dosage should be adjusted gradually with 2-3 days between dosing increments in order to achieve steady state and to allow monitoring of QT intervals. Graded dose adjustment will help prevent the use of dosages which are higher than necessary. The recommended initial dosing schedule is 160mg daily taken in two divided doses at approximately 12 hour intervals. This dose may be increased if necessary to 240 or 320mg per day. In most patients a therapeutic response is obtained at a daily dose of 160-320mg per day given in two divided doses. However some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480-640mg per day. These doses should only be prescribed when the potential benefit outweighs the increased risk of adverse events particularly proarrhythmias.
Because sotalol is excreted mainly by the kidneys a dosage adjustment should be made. A possible dosing schedule is given in the table below:
| Creatinine Clearance (mL/min) | Dosing Reccomendation |
|---|---|
| >60 | Usual dosage |
| 30-60 | Half usual dosage |
| 10-30 | Quarter usual dosage |
| <10 | Avoid or use with caution |
The safety and effectiveness of APO-SOTALOL in children has not been established.
Bronchospasm e.g. bronchial asthma or chronic obstructive airway disease.
Allergic disorders including allergic rhinitis which may suggest a predisposition to bronchospasm.
Right ventricular failures secondary to pulmonary hypertension.
Significant right ventricular hypertrophy.
Sinus bradycardia - less than 45-50 beats per minutes.
Second and third degree A-V block or sick sinus syndrome unless a functioning pacemaker is present.
Shock including cardiogenic and hypovolaemic shock.
Uncontrolled congestive heart failure.
Severe renal impairment - Creatinine clearance <10mL/min.
Congenital or acquired long QT syndromes.
Hypersensitivity to sotalol hydrochloride or any other constituent of the tablets.
The most dangerous adverse effect of antiarrhythmic drugs is the aggravation of pre-existing arrhythmias or the provocation of new arrhythmias. Drugs that prolong the QT interval may cause torsade de pointes, a polymorphic ventricular tachycardia. There is increased risk of the occurrence of torsades de pointes in association with prolongation of the QT interval, reduction in heart rate, reduction in serum potassium and magnesium (e.g.: as a consequence of diuretic use), high plasma drug concentrations (e.g.: as a consequence of overdosage or renal insufficiency), and with the concomitant use of sotalol hydrochloride and other medications such as antidepressants and Class 1 antiarrhythmics which have been associated with torsades de pointes. Other risk factors include gender (females have a higher incidence) and a history of cardiomegaly or congestive heart failure. ECG monitoring immediately prior to or following the episodes usually reveals a significantly prolonged QT interval and a significantly prolonged QTc interval. APO-SOTALOL should be titrated very carefully in patients with prolonged QT intervals.
Serious pro-arrhythmias including torsades de pointes appear to be dose related. 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 also with every upward dose adjustment; events tend to occur within 7 days of initiating therapy or with an increase in dose. Initiating therapy at 80mg twice a day with gradual upward dose titration thereafter, and appropriate evaluations for efficacy and safety prior to dose escalation, reduces the risk of proarrhythmia. APO-SOTALOL should be used with particular caution if the QTc is greater than 500msec on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc interval exceeds 550msec. Due to the multiple risk factors associated with torsade de pointes however, caution should be exercised regardless of the QTc interval.
Beta-blockers 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 - a low initial dose and careful dose titration is appropriate.
Caution should be exercised when APO-SOTALOL is given to patients with recent myocardial infarction. Experience in the use of sotalol hydrochloride in the early stage of recovery from acute MI is limited and, at least at higher initial doses, not reassuring. Careful dose titration is especially important, particularly in patients with impaired left ventricular function where the risk versus the benefit must be carefully assessed before commencing therapy.
Patients should be warned against abrupt interruption or discontinuation of APO-SOTALOL. Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Occasional cases of severe exacerbation of angina pectoris, ventricular arrhythmias and in some cases myocardial infarction have also been reported after 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 APO-SOTALOL, particularly in patients with ischemic heart disease, to carefully monitor the patient and to discontinue APO-SOTALOL in a step-wise 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 one to two weeks - the same frequency of administration should be maintained. Because coronary artery disease is common and may be unrecognised in patients receiving APO-SOTALOL, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.
Concomitant use of calcium channel blockers and beta-blockers may result in hypotension, bradycardia, conduction defects and cardiac failure. Beta channel blockers should be avoided in combination with cardiodepressant calcium channel blockers because of the additive effect on atrioventricular conduction and ventricular function.
Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease.
Interactions have been reported during concomitant beta-blocker therapy with Class IA disopyramide and less frequently quinidine, Class IB tocainide, mexiletine and lignocaine, Class IC flecainide and propafenone, Class III amiodarone and Class IV antiarrhythmic agents. Concomitant use of these agents and sotalol is not recommended.
There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a beta-blocker. Such treatment should only be undertaken in a Coronary or Intensive Care Unit.
The effect of beta-blockers on thyroid metabolism may result in elevations of serum-free thyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism additional investigation is necessary before a diagnosis of thyrotoxicosis can be made.
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.
Although it is not advisable to withdraw APO-SOTALOL prior to surgery in the majority of patients, caution is advised in patients undergoing surgery, particularly with anaesthetics that cause myocardial depression such as cyclopropane or trichloroethylene. Vagal dominance, if it occurs, may be corrected with atropine (1-2mg I.V.). Some patients receiving beta-blockers have been subject to protracted severe hypotension during anaesthesia. Difficulty in restarting the heart and maintaining the heart beat has also been reported. In emergency surgery, since sotalol hydrochloride is a competitive agonist at beta-adrenoreceptor sites, its effects may be reversed if required by sufficient doses of such agonists as isoproterenol or noradrenaline.
In patients with diabetes mellitus (especially labile diabetes) or with a history or episodes of spontaneous hypoglycaemia, APO-SOTALOL should be given with caution since beta blockade may mask some important premonitory signs of acute hypoglycaemia e.g.: tachycardia.
Beta adrenoreceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some drugs affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect appears to be less for drugs with intrinsic sympathomimetic activity.
Renal function tests should be carried out at appropriate intervals. Caution should be observed in patients with impaired renal function since APO-SOTALOL 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 rate of sotalol hydrochloride. Dosage adjustment may be required. Sotalol is contraindicated in patients with severe renal impairment.
Concomitant use with drugs such as reserpine and guanethidine requires careful monitoring since the added effect of a beta-blocker may produce an excessive reduction of the resting sympathetic nervous tone.
Concurrent use of clonidine and beta-blockers should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker.
In patients with this condition, an alpha-blocking agent e.g. phentolamine/phenoxybenzamine should be administered before the beta-blocker to avoid exacerbation of hypertension.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers. Cross reactions may occur between beta-blockers therefore substitutions within the group may not necessarily preclude occurrence of symptoms.
Allergic reactions may be exaggerated by beta-blockade. Beta-blockers should be avoided if there is a risk of bronchospasm.
Beta-blockers may mask the clinical signs (e.g.: tachycardia) 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 APO-SOTALOL which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.
Excessive prolongation of the QT interval (>550msec) can promote serious arrhythmias and should be avoided. Sinus bradycardia (heart rate less than 50 bpm) can occur, and this in itself increases the risk of torsades de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients, and the incidence of 2nd or 3rd degree AV block is approximately 1%.
APO-SOTALOL should not be used in patients with existing hypokalemia or hypomagnesemia 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 diarrhoea or patients receiving concomitant magnesium and/or potassium-depleting drugs.
If excessive bradycardia occurs either alone or with hypotension, atropine 0.5 to 2mg should be given intravenously and immediately followed if necessary by a beta-receptor stimulating agent e.g. isoprenaline. If patients experience this effect in initial administration of APO-SOTALOL therapy should be temporarily stopped. APO-SOTALOL may be re-introduced later at a lower dose. A reduction in dose by 80 or 160mg per day may be advisable to alleviate symptoms of weakness and dizziness in cases where the blood pressure continues to fall after a month or two of APO-SOTALOL.
Beta blocking agents have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.
Category C
Sotalol has been shown to cross the placental barrier and cause bradycardia in the foetus and newborn infant. There has been a report of subnormal birth weight with sotalol. It should only be used in the late stages of pregnancy after weighing the needs of the mother against the risk to the foetus.
Sotalol is actively excreted in breast milk (milk/plasma ratio = 5.4/1) and therefore should not be administered to breastfeeding mothers.
APO-SOTALOL is well tolerated in the majority of patients with the most frequent adverse events arising from its beta blockade properties. Adverse reactions are usually transient in nature and rarely necessitate interruption of or withdrawal from treatment. These include dyspnoea, fatigue, dizziness, headache, fever, bradycardia and/or hypotension. If they do occur these side effects usually resolve when dosage is reduced.
The most significant adverse events are those due to proarrhythmia, including torsades de pointes
In clinical trials discontinuation due to unacceptable adverse effects was necessary in 18% of all patients in cardiac arrhythmia trials. The most common adverse events leading to discontinuation were fatigue 4%, bradycardia 3%, dyspnoea 3%, proarrhythmia 2%, asthenia 2% and dizziness 2%.
>1% : changes in plasma lipid concentrations
<1% : changes in antinuclear factor (ANF) titres have been reported but the clinical significance is unclear.
>1% : Ventricular tachyarrhythmias, torsades de pointes, chest pain, bradycardia, hypotension, cold extremities, dyspnoea, palpitations, oedema, ECG abnormalities, proarrhythmia, syncope, heart failure, presyncope. Hypotension and bradycardia are more frequent after intravenous administration.
<1% : Congestive heart failure, prolonged QT interval. Increased ventricular ectopic beat frequency, cardiogenic shock and AV block (1) have been observed after intravenous administration.
>1% : Rash
<1% : Cutaneous thickening, pruritus.
>1% : Diarrhoea, nausea/vomiting, flatulence, dyspepsia, abdominal pain.
>1% : Headache, tiredness, fever.
>1% : Dizziness, drowsiness, lethargy, weakness, vertigo, lightheadedness, headache, sleep disturbances, depression, parathesia, mood changes, anxiety.
>1% : Visual disturbances including eye irritation, deterioration of eyesight, blurred vision and photophobia, taste abnormalities, hearing disturbances.
>1% : Sexual dysfunction.
>1% : Shortness of breath.
<1% : Unusual dreams.
<1% : Retropertoneal fibrosis, facial atrophy.
Myocardial insufficiency may require treatment with digitalis and diuretics. Bradycardia may respond to atropine. Bronchospasm may be reversed with a β2 stimulant. Severe hypotension may require use of a vasopressor. Cardiac infarction following abrupt withdrawal of APO-SOTALOL from patients with ischaemic heart disease can be avoided by a gradual reduction of the dose. Temporary overdrive pacing is suggested as treatment of ventricular arrhythmias in association with prolonged QT interval.
The plasma clearance of sotalol is reduced after alcohol ingestion.
Hyperglycaemia and hypoglycaemia may occur, and the dosage of antidiabetic agents may require adjustment. Symptoms of hypoglycaemia may be masked by APO-SOTALOL.
Agents such as ether, chloroform and cyclopropane are contraindicated with sotalol.
Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with APO-SOTALOL.
Concurrent administration of beta-adrenergic blocking agents and calcium channel blockers have resulted in hypotension, bradycardia, conduction defects and cardiac failure. Beta-blockers should be avoided in combination with cardiodepressant calcium channel blockers because of the additive effects on atrioventricular conduction and ventricular function.
Concomitant use of catecholamine-depleting agents such as reserpine and guanethidine with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients treated with APO-SOTALOL plus a catecholamine depletor should be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope.
Beta blocking agents 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.
APO-SOTALOL should be given with extreme caution in conjunction with other agents 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.
Class IA antiarrhythmic agents such as disopyramide, quinidine and procainamide, and Class III drugs such as amiodarone, are not recommended as concomitant therapy with APO-SOTALOL because of their potential to prolong refractoriness. The concomitant use of other beta blocking agents with APO-SOTALOL may result in additive Class II effects.
Hypokalemia and hypomagnesemia may occur, increasing the potential for torsades de pointes.
Single and multiple doses of APO-SOTALOL do not significantly affect serum digoxin levels. Proarrhythmic events were more common in sotalol hydrochloride treated patients also receiving digoxin however; this may be related to the presence of congestive heart failure, a known risk factor for proarrhythmia, in the patients receiving digoxin.
The presence of sotalol hydrochloride 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 APO-SOTALOL should have their urine screened utilising the high performance liquid chromatographic assay with solid phase extraction.
Cases of sotalol intoxication including one fatality have been reported
Symptoms include asystole, severe bradycardia, congestive heart failure, hypotension, prolongation of QT interval, ventricular tachyarrhythmias, torsades de pointes, hypoglycaemia and bronchospasm.
Close monitoring of the electrocardiogram in patients with suspected sotalol intoxication is recommended. Every effort should be made to correct promptly metabolic and electrolyte imbalances which might contribute to the initiation of ventricular arrhythmias.
Gastric lavage and activated charcoal should be administered when an overdose of APO-SOTALOL is suspected. Bradycardia and hypotension should be corrected prior to gastric lavage or endotracheal intubation as these procedures may increase vagal tone.
Depending upon the symptoms the following therapeutic measures are suggested:
Atropine 1-2mg intravenously may be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline may be given. An appropriate regime would be 5mcg bolus, followed by an infusion of 0.5-10mcg per minute, titrated to achieve the desired effect. In refractory cases the use of a cardiac pacemaker should be considered.
Transvenous cardiac pacing.
Severe hypotension should respond to a sympathomimetic amine e.g. isoprenaline or noradrenaline. In refractory cases the use of glucagon hydrochloride should be considered.
DC cardioversion, transvenous cardiac pacing, adrenaline and/or I.V. magnesium sulphate.
A beta-2-agonist and/or aminophylline.
Dialysis lowers the plasma sotalol concentration by approximately 20%.
Store below 25°C.
Protect from heat, light and moisture.
Prescription Only Medicine
Bottles packs of 60,100, 500 and 1000 tablets
Blister packs of 60, 100, 500 and 1000 tablets
Tablets contain dextrates and indigo carmine as a colourant.
Apotex NZ Ltd.
32 Hillside Road
Glenfield
Private Bag 102-995
North Shore Mail Centre
Auckland
Telephone: (09) 444-2073
25 August 2000