SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sotalol 80 mg Tablets

2. Qualitative and Quantitative Composition

Each scored tablet contains 80 mg of sotalol hydrochloride. For a full list of excipients, see section 6.1.

3.    Pharmaceutical form

Tablet.

80 mg: Light blue, oval-shaped tablet, scored on one side and debossed with the

number “93” and “61” on each side of the score, plain on the other side

The tablet can be divided into equal halves.

4.    CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of:

-    life-threatening ventricular tachycardias;

-    documented symptomatic and disabling ventricular tachycardias in the absence of uncontrolled heart failure;

-    documented supraventricular tachycardias in the absence of uncontrolled heart failure when the need for treatment is established. (e.g. maintenance of sinus rhythm after conversion of atrial fibrillation or atrial flutter.)

4.2. Posology and method of administration

The initiation of treatment or change in dosage should follow an appropriate medical evaluation, including ECG control with measurement of the corrected QT interval and potassium levels, assessment of renal function and taking into account concomitant medication (see section 4.5.).

As with other antiarrhythmic substances, it is recommended that Sotalol Teva Pharma is initiated and doses increased under ECG control, because proarrhythmic events can occur not only at the initiation of therapy but also with every upward dosage adjustment.

The treatment of life-threatening ventricular tachycardias must be initiated under monitoring in a hospital environment.

The initial dose is 80 mg administered either as a single or as two divided doses administered at 12 hours interval. Dosing increments should be separated by an interval of 2 or 3 days in order to attain a steady state and allow monitoring of QT intervals.

Most patients respond to a daily dose of 160 to 320 mg in two (e.g. 2x 160 mg) or three (e.g. 3x 80 mg) divided doses per day.

Some patients who have life-threatening arrhythmias may require doses as high as 480 mg or 640 mg/day; however, these doses should only be prescribed when the potential benefit outweighs the increased risk of adverse events, in particular proarrhythmia.

Dosage in renally impaired patients: the dosage should be adjusted according to the creatinine clearance, because sotalol is excreted mainly in urine. The heart rate (should not fall below 50 beats per minute) and the clinical effect should also be considered.

Creatinine Clearance (ml/min)	Recommended posology
> 60	Usual dose
30 - 60	Half-dose
10 - 30	Quarter dose
< 10	Avoid sotalol

Cockcroft & Gault formula:

Men:

(140 - age) x weight (kg)

72 x serum creatinine (mg/dl)

Women: idem x 0.85.

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

Dosage in hepatically impaired patients:

No dosage adjustment is required.

Elderly:

Age in itself is not a reason to adapt the initial dosage. Reduction in renal function due to old age may necessitate dose adaptation (see also Dosage in renal insufficiency).

Children:

Due to lack of data, sotalol is not intended for use in children.

The tablets should be taken with a sufficient amount of liquid (e.g. a glass of water) and swallowed whole.

4.3. Contra-indications

Sotalol is contra-indicated in the following situations:

-    long QT syndromes (congenital or acquired)

-    torsades de pointes

-    known hypersensitivity to sotalol, sulfonamides or any of the excipients of the formulation

-    bronchial asthma and chronic obstructive airway disease

-    uncontrolled heart failure

-    cardiogenic shock

-    2^nd and 3^nd degree atrioventricular heart block, unless a functioning pacemaker is present

-    Prinzmetal angina pectoris

-    sick sinus syndrome (including sino-atrial heart block) unless a functioning pacemaker is present

-    bradycardia (< 50 beats/minute)

-    Raynaud’s phenomenon and peripheral circulatory disturbances

-    untreated phaeochromocytoma

-    arterial hypotension (except when due to arrhythmia)

-    anaesthesia that produces myocardial depression

-    severe renal failure (creatinine clearance < 10 ml/min)

-    metabolic acidosis

-    combination with substances that cause torsades de pointes:

• class    Ia anti arrhythmic agents (quinidine, hydroquinidine, disopyramide...),

•    other class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide...),

•    some neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol...),

• other    active substances    e.g. bepridil, cisapride, diphenamil,

erythromycin IV, mizolastine, vincamine IV, moxifloxacin.

-    floctafenine (see section 4.5.).

4.4. Special warnings and special precautions for use

Warnings_

Never withdraw the treatment abruptly in patients with angina pectoris: this could cause severe arrhythmias, myocardial infarction and sudden death, or could unmask latent coronary heart disease.

It is recommended to monitor patients, especially those suffering from ischaemic heart disease, and to decrease the dose gradually over 1-2 weeks.

The incidence of torsades de pointes is dose-dependent. Proarrhythmic events occur more often within the first week of treatment initiation or dose escalation. However, they may occur after a longer period of treatment even without any dose change. They may be symptomatic (syncopes), they may discontinue spontaneously or more rarely progress to ventricular fibrillation.

In clinical trials of patients with ventricular arrhythmias carrying a life-threatening risk (sustained ventricular tachycardias or ventricular fibrillation), the incidence of severe proarrhythmias (torsades de pointes or new ventricular tachycardias or ventricular fibrillation) was less than 2 % at doses up to 320 mg. The incidence is more than doubled for higher doses.

The highest risk of developing severe proarrhythmic events with sotalol (7%) occurs in patients with sustained ventricular tachycardia and heart failure. The risk of proarrhythmic events may be reduced by initiating therapy with 80 mg, with gradual upward dose titration thereafter.

During therapy, medical monitoring and ECG controls should be performed at regular intervals. If the ECG parameters deteriorate (e.g. 25% or greater prolongation of the QRS or QT interval, 50% or greater prolongation of the PQ interval or if the QTc interval exceeds 480 ms) or if the frequency and severity of arrhythmias increase, a re-evaluation of the benefit/risk ratio should be considered.

As this product contains lactose, it is unsuitable for patients with congenital galactosaemia, glucose/galactose malabsorption syndrome or lactase deficiency.

Precautions for use

-    Bradycardia

If heart rate drops to below 50-55 beats per minute at rest and the patient shows symptoms associated with bradycardia, the posology must be reduced. Bradycardia increases the risk of torsades de pointes.

-    First degree atrioventricular heart block

Given its negative dromotropic effect, sotalol should be administered with caution to patients with first degree atrioventricular heart block.

-    Heart failure

Caution is advised when initiating sotalol therapy or during adjustment of dose, in patients with left ventricular dysfunction controlled by therapy (such as angiotensin converting enzyme inhibitors, diuretics, digitalis...).

Due to its beta-blockade properties, sotalol can further depress myocardial contractility and precipitate sudden decompensation of severe cardiac failure.

-    Recent myocardial infarction

The benefit/risk ratio of sotalol administration should be evaluated in postinfarction patients, with impaired left ventricular function. If this treatment is deemed necessary, its initiation and any subsequent changes in posology must be carefully monitored. Sotalol should be avoided in patients with left ventricular ejection fraction <40% without serious ventricular arrhythmia.

-    Electrolytic disturbances

Sotalol should not be used in patients with hypokalaemia or hypomagnesaemia prior to correction of the imbalance. The electrolytic and acid-base balance must be closely monitored in patients with severe or prolonged diarrhoea or patients receiving concomitant magnesium- and/or potassium-depleting medicinal products.

-    Anaphylaxis

Due to its beta-blockade properties, sotalol may aggravate anaphylactic reactions and cause resistance to treatment by the usual doses of adrenaline in patients prone to severe anaphylactic reactions, whatever their origin, and especially if they are due to floctafenine or iodised contrast media (see section 4.5.) or occur during desensitisation therapy.

-    Thyrotoxicosis

Due to its beta-blockade properties, sotalol can mask the cardiovascular signs of thyrotoxicosis.

-    Psoriasis

As exacerbation of this illness has been reported with beta-blockers, the indication needs to be weighed up.

-    Geriatric patients

The contra-indications must imperatively be respected. Effort should be made to initiate treatment with a low dose and to ensure strict follow-up.

-    Renal impairment

In patients with renal impairment, the dose should be adjusted according to renal function.

-    Diabetes mellitus

Inform the patient and reinforce glycaemic auto-monitoring at the initiation of treatment. The precursor signs of hypoglycaemia may be masked, in particular tachycardia, palpitations and sweating.

-    Electrocardiographic changes

Strict monitoring and re-evaluation of the benefit/risk ratio are required if excessive QTc-interval prolongation (> 480 ms) is observed. The risk of torsades de pointes is proportional to the degree of QT interval prolongation.

-    General anaesthesia

Due to its beta-blockade properties, sotalol can decrease reflex tachycardia and increase the risk of hypotension. Continuation of treatment with sotalol reduces the risk of arrhythmia, myocardial ischaemia and hypertension crises. The anaesthetist should be informed that the patient is being treated with sotalol.

If it is judged necessary to discontinue the treatment, a 48 hour withdrawal is considered sufficient to allow sensitivity to catecholamines to re-develop. In certain cases, treatment with sotalol cannot be interrupted.

In patients suffering from ischaemic heart disease or coronary heart disease, it is preferable to continue the treatment up to the intervention, given the risk associated with abrupt discontinuation of beta-blockers.

In urgent cases or if it is impossible to stop the treatment, the patient should be protected from vagal predominance by sufficient atropine pre-medication, renewed according to requirements.

The anaesthetics used should have minimal myocardial depressive action, and any blood loss should be compensated for.

-    Sotalol IS GENERALLY NOT RECOMMENDED in combination with halofantrine, pentamidine, sparfloxacin or methadone (see section 4.5.), and during lactation.

-    Sotalol is generally not recommended in association with certain medicinal products (see section 4.5, "Combinations not recommended").

-    It is also not recommended with drugs which can induce hypertension (e.g. MAOIs).

4.5 Interactions with other medicinal products and other forms of interaction

The special properties of sotalol may cause serious arrhythmias (torsades de pointes), particularly in the presence of hypokalaemia and/or bradycardia. In terms of interactions with other medicinal products, it should be considered as an antiarrhythmic agent. Combination with other such agents is therefore VERY DELICATE, if not CONTRA-INDICATED, and requires close clinical and ECG monitoring.

Contra-indicated combinations

-    Floctafenine: in case of floctafenine-induced shock or hypotension, sotalol impedes the compensatory cardiovascular reactions.

-    Torsades de pointes-inducing agents: class Ia antiarrhythmic active substances (quinidine, hydroquinidine, disopyramide) and class III antiarrhythmic active substances (amiodarone, dofetilide, ibutilide...), some neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride,

tiapride, pimozide, haloperidol, droperidol...), bepridil, cisapride, diphemanil, erythomycin IV, mizolastine, vincamine IV, moxifloxacin ...

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Combinations not recommended

-    Halofantrine, pentamidine, sparfloxacin, methadone: increased risk of ventricular arrhythmias, particularly torsades de pointes.

-    If possible, the torsades de pointes-inducing medicinal product should be discontinued, unless it is an anti-infective agent. If the combination is unavoidable, the QT interval should be measured beforehand and the ECG monitored.

-    Diltiazem, verapamil:

As with other beta-blockers, automatism disorders (excessive bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disorders, heart failure (effect synergy) may occur. Such a combination should only be used with close clinical and ECG monitoring, especially in the elderly, and at the initiation of therapy.

Associations requiring precautions for use:

-    Active substances causing hypokaleamia (potassium-depleting diuretics, stimulant laxatives, glucocorticoids, tetracosactide, amphotericin B (IV)): increased risk of ventricular arrhythmias, in particular torsades de pointes.

Any decrease in potassium levels should be corrected before the product is administered. Clinical, electrolytic and ECG monitoring is necessary.

-    Bradycardia-inducing active substances (bradycardia-inducing calcium antagonists: diltiazem, verapamil; centrally-acting antihypertensive agents such as clonidine, guanfacine, alpha-methyldopa; digitalis glycosides including digoxin; class Ia and Ic antiarrhythmic agents; mefloquine; cholinesterase inhibitors such as those used in Alzheimer’s disease e.g. donepezil, rivastigmine, tacrine, galantamine, neostigmine, pyridostigmine, ambemonium; pilocarpine, other beta-blocking agents)

Increased risk of ventricular arrhythmias, in particular torsades de pointes, due to the torsades de pointes-inducing properties of sotalol.

Clinical and ECG monitoring required.

Additionally, for centrally-acting antihypertensive agents, rebound hypertension may occur if they are withdrawn abruptly.

-    Volatile halogenated anaesthetics: Sotalol reduces the compensatory cardiovascular response (beta-agonists may be used during the procedure to overcome the beta-blockade).

As a general rule, sotalol should not be withdrawn, and must never be discontinued abruptly.

The anaesthetist must be informed that the patient is receiving sotalol.

-    Insulin, hypoglycaemic sulphonamides: All beta-blockers can mask certain symptoms of hypoglycaemia: palpitations and tachycardia. Most non-cardioselective beta-blockers increase the incidence and severity of hypoglycaemia.

Inform the patient and re-inforce automonitoring of the blood, especially at the initiation of therapy.

-    Propafenone: Contractility, automatism and conduction disorders (inhibition of compensatory sympathetic mechanisms).

Clinical and ECG monitoring required.

-    Baclofen: Increased antihypertensive effect.

Blood pressure should be monitored and the antihypertensive dosage adjusted if necessary.

-    Lidocaine (administered intravenously): Increased lidocaine plasma levels, with possible cardiac and neurological adverse effects (decreased hepatic clearance of lidocaine).

Clinical and ECG monitoring required.

Associations to be taken into account:

-    NSAIDs (extrapolated from indomethacin): Decreased antihypertensive effect (NSAIDs inhibited the vasodilator prostaglandins; pyrazole NSAIDs cause sodium and water retention).

-    Imipramine antidepressants (tricyclics), phenothiazine neuroleptics, amifostine: Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).

-    Calcium channel-blocking active substances (dihydropyridines):

hypotension, cardiac failure in patients with latent or uncontrolled cardiac failure (negative inotropic effect of dihydropyridines (in vitro), more or less marked depending on the product, and prone to add to the negative inotropic effect of sotalol). The presence of sotalol can also minimise the sympathetic reflex reaction arising due to excessive haemodynamic repercussion.

-    Dipyridamole (administered intravenously): Increased antihypertensive effect.

-    Interactions with laboratory tests:

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine, when measured by a photometric method. The urine of sotalol-treated patients suspected of having phaeochromocytoma should be analysed using the HPLC assay with solid phase extraction.

-    Athletes should be warned of the fact that this medicine contains an active substance which can induce a positive reaction in drug tests.

4.6. Pregnancy and lactation Pregnancy

There are no well-controlled studies on the use of sotalol in pregnant women. Animal studies with sotalol hydrochloride have shown no evidence of teratogenicity or other harmful effects on the foetus after use of sotalol at therapeutic doses

In humans, sotalol crosses the placenta. Due to its pharmacological properties, adverse effects may occur in the foetus and neonate, after use of sotalol later in pregnancy.

In neonates born to mothers treated with sotalol, the beta-blocking action of the drug can still be present several days after birth. It may manifest as bradycardia, respiratory distress or hypoglycaemia. In general, this fact is clinically insignificant. However, it is possible that, by reducing compensatory cardiovascular reactions, cardiac failure requiring hospitalisation and intensive care may occur (see section 4.9.). In such cases, plasma expanders should be avoided (risk of acute pulmonary oedema).

Consequently, sotalol may be administered during pregnancy only if needed. The neonate should be monitored very carefully for 48-72 hours after delivery if it was not possible to terminate maternal therapy with sotalol 2-3 days before the birth date.

Lactation

Sotalol is transferred to breast milk in relatively large quantifies.

Hypoglycaemia and bradycardia have been reported to occur in breast-fed children whose mothers are treated with some beta-blockers that bind little to plasma proteins. Consequently, breast-feeding is not recommended during the course of treatment.

4.7 Effects on ability to drive and use machines

Sotalol can influence individual reactions to such an extent that the ability to take an active part in road traffic or to operate machines or work without suitable safeguards may be impaired.

4.8 Undesirable effects

Clinical

The most frequent undesirable effects of sotalol arise from its beta-blockade properties. They are usually transient in nature, and rarely require discontinuation of the treatment. They usually disappear when the dosage is reduced. The most serious undesirable effects are those due to proarrhythmic effects, including torsades de pointes (see section 4.4.).

The most frequent undesirable effects are:

-    Blood and lymphatic system disorders: thrombocytopenia, eosinophilia, leucopenia;

-    Metabolism and nutrition disorders: hypoglycaemia;

-    Psychiatric disorders: depression, anxiety;

-    Nervous system disorders: dizziness, headaches, sleep disturbances, paraesthesia, fatigue, asthenia

-    Eye disorders: visual disorders;

-    Cardiovascular disorders: sinus bradycardia, atrioventricular conduction disorders, dyspnoea, chest pain, palpitations, redema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope, Raynaud’s syndrome; aggravation of existing intermittent claudication;

-    Respiratory, thoracic and mediastinal disorders: bronchonconstriction, dyspnoea, in particular in patients with obstructive ventilation disorders;

-    Gastrointestinal disorders: nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence;

-    Skin and subcutaneous tissue disorders: various cutaneous manifestations, including psoriasis-like eruptions or exacerbation of psoriasis (see section 4.4.), exanthema, rash, pruritus, photosensitivity, diaphoresis;

-    Musculoskeletal, connective tissue and bone disorders: cramps, arthralgia, myalgia;

-    Reproductive system and breast disorders: disorders of sexual function;

Investigations

In rare cases, formation of anti-nuclear anti-bodies has been reported, only exceptionally accompanied by clinical manifestations of lupus-like syndrome which disappear when the treatment is discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Accidental or intentional overdosage with sotalol has rarely resulted in death. Haemodialysis results in a large reduction of plasma levels of sotalol.

The commonest signs of overdose are as follows: bradycardia, congestive heart failure, hypotension, bronchospasm, hypoglycaemia.

In cases of massive intentional overdosage (2-16 g) of sotalol, the following clinical findings have been reported: hypotension, bradycardia, atrioventricular heart block, QT interval prolongation, premature ventricular complexes, ventricular tachycardia, torsades de pointes.

In case of:

-    bradycardia or excessive decrease in blood pressure, 0.5-2 mg IV atropine and 1 mg glucagon should be administered, followed if necessary by a slow injection of 25 micrograms isoprenaline or 2.5-10 micrograms/kg/min dobutamine. Further doses of glucagon may be administered if necessary;

-    2^nd or 3^nd degree atrioventricular block: treatment by transmural cardiac pacing;

-    bronchospasm: treatment with theophylline or p₂-receptor-stimulant aerosol.

-    Torsades de pointes: treatment with cardioversion, transmural cardiac pacing and/or magnesium sulphate.

In case of cardiac decompensation in neonates, where the mother was being treated with sotalol:

-    0.3 mg/kg glucagon;

-    hospitalisation in intensive care;

-    isoprenaline and dobutamine: as the posologies are generally high and the treatment prolonged, specialised monitoring is necessary (see section 4.6.).

Overdose is associated with a risk of serious ventricular arrhythmias (torsades de pointes).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-blocking agents, non-selective - Sotalol ATC code: C07A A07

Sotalol is an antiarrhythmic agent with both class II properties (non-selective beta-adrenergic receptor blocking agent, devoid of intrinsic sympathomimetic activity or membrane stabilising activity) and class III properties (prolongation of duration of cardiac action potential).

Electrophysiology

Sotalol decreases heart rate and atrioventricular conduction velocity (PR interval prolongation), increases the refractory period of the atrioventricular junction, increases QT & QTc intervals, without altering ventricular depolarisation (no significant changes in QRS duration). It prolongs the atrial, ventricular and accessory pathway refractory periods (in the anterograde and retrograde directions).

Haemodynamics

Due to its beta-blockade properties, sotalol has negative inotropic effects. Conversely, its class III properties cause a positive inotropic effect. Even though sotalol is usually well tolerated from a haemodynamic point of view, caution is recommended in the presence of altered ventricular function.

Like other beta-blockers, sotalol produces a reduction in both systolic and diastolic blood pressure in hypertensive patients.

5.2. Pharmacokinetic properties

Absorption

The maximum plasma concentration is reached in 2.5 to 4 hours after oral administration and the plasma steady state is reached in 2 to 3 days. Bioavailability is greater than 90% and shows very little inter-individual variation. Good correlation can be noted between the dose administered and the plasma concentrations. Bioavailability is reduced by approximately 20 % when the product is administered with a meal.

Distribution

The apparent volume of distribution is 1.2 to 2.4 l/kg. Protein binding is negligible, facilitating tissue diffusion of sotalol.

Penetration across the blood-brain barrier is poor (cerebrospinal fluid concentration < 10% of plasma concentration).

Metabolism

Sotalol is not metabolised.

Plasma half-life

10 to 20 hours in a subject with normal renal function.

Excretion

Sotalol is eliminated by renal excretion. Approximately 80 to 90% of the dose administered is excreted unchanged in the urine. Dosage adjustment is necessary in conditions of renal impairment (see section 4.2.).

Age does not significantly change the pharmacokinetic parameters even though renal function in geriatric patients may decrease elimination, resulting in increased accumulation of sotalol.

Passage across the placental barrier

Sotalol passes the placental barrier. The ratio between the umbilical cord blood concentration and the maternal blood concentration is 1.05/1.

Excretion in milk is high. The ratio between the concentration in the mother’s milk and plasma is 5/1.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Lactose monohydrate Maize starch Indigo carmine (E132)

Povidone (K-30)

Magnesium stearate

6.2. Incompatibilities

Not applicable

6.3. Shelf life

3 years

6.4. Special precautions for storage

Keep container in the outer carton in order to protect from light.

6.5. Nature and contents of container

PVC/PVdC/aluminium blisters containing 20, 28, 30, 40, 50, 60, 90 and 100 scored tablets. 50 tablets in EAV blisters (hospital packs)

Not all pack sizes may be marketed.

6.6. Instructions for use and handling and disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

UK: TEVA UK Limited

Brampton Road, Hampden Park Eastbourne BN22 9AG

8.    MARKETING AUTHORISATION NUMBER

PL 00289/0389

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/09/2006

10    DATE OF REVISION OF THE TEXT

03/06/2015