Active ingredients: Sotalol (Sotalol hydrochloride)
SOTALEX 80 mg tablets
Why is Sotalex used? What is it for?
Pharmacotherapeutic group
Non-selective, non-associated beta-blockers.
THERAPEUTIC INDICATIONS
SOTALEX is indicated in the prophylaxis of paroxysmal supraventricular tachyarrhythmias, in the maintenance of sinus rhythm after conversion of atrial flutter / fibrillation, in threatening or symptomatic ventricular tachyarrhythmias.
Contraindications When Sotalex should not be used
SOTALEX is contraindicated in patients with:
- Bronchial asthma or chronic obstructive diseases of the respiratory system.
- Hypersensitivity to the active substance or to any of the excipients.
- Cardiogenic shock
- Anesthesia inducing myocardial depression.
- Symptomatic sinus bradycardia.
- Sinus node syndrome, degree II and III atrioventricular block (unless a pacemaker is installed).
- Uncontrolled heart failure.
- Renal insufficiency (Creatinine clearance <10 ml / min)
- Long QT syndrome (congenital or acquired).
- Metabolic acidosis
- Untreated pheochromocytoma
- Hypotension
- Raynaud's phenomenon and severe disorders of the peripheral circulation
Precautions for use What you need to know before taking Sotalex
Anesthesia: in the course of surgical interventions conducted with myocardial depressive anesthetics (eg cyclopropane, trichlorethylene) it is necessary to administer beta-blocking drugs with caution.
Diabetes mellitus: In patients with diabetes mellitus (especially if not well compensated) or with previous episodes of spontaneous hypoglycaemia, SOTALEX should be administered with caution as beta-blockers may mask some important warning signs of hypoglycaemia (e.g. tachycardia). Thyrotoxicosis: Beta-blocker may mask some clinical signs (e.g. tachycardia) of hyperthyroidism. Patients with suspected hyperthyroidism should avoid abrupt discontinuation of therapy, which may be followed by worsening of symptoms, including thyrotoxic storm.
Hepatic dysfunction: patients with impaired liver function do not show reductions in elimination of SOTALEX, since the drug is not subject to the phenomenon of first pass metabolism.
Renal dysfunction: SOTALEX is eliminated primarily via the kidney, by glomerular filtration and minimally by tubular secretion. There is a direct correlation between renal function, assessed on the basis of serum creatinine and / or creatinine clearance, and the elimination half-life of SOTALEX. and time of administration ".
Psoriasis: Beta-blockers have rarely been reported to induce worsening of the symptoms of Psoriasis Vulgaris.
Interactions Which drugs or foods may change the effect of Sotalex
Antiarrhythmics: Class Ia antiarrhythmic drugs (e.g. diisopyramide, quinidine and procainamide) and Class III drugs (e.g. amiodarone) are not recommended as concomitant therapy with SOTALEX due to their ability to prolong the refractory period (see Special Warnings) . Co-administration of other beta-blockers with SOTALEX may give an additive Class II effect.
Potassium-depleting diuretics: These drugs can induce hypokalaemia or hypomagnesaemia, increasing the risk of Torsades de Pointes (see Special Warnings - Electrolyte Disorders). Potassium depleting drugs: iv amphotericin B, systemic corticosteroids, and some laxative compounds, can induce hypokalaemia; blood potassium levels should be monitored and possibly corrected while using SOTALEX.
Drugs that prolong the QT interval: SOTALEX should be administered with extreme caution together with other drugs that prolong the QT interval such as Class I antiarrhythmics, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, and some quinolone antibiotics ( see Special Warnings).
Digoxin: Single and multiple doses of SOTALEX do not significantly change digoxin levels. Proarrhythmic events are more frequent in patients treated simultaneously with sotalol and digoxin; however this may be justified, in patients receiving digoxin, by the presence of heart failure, a known risk factor for proarrhythmic events.
Calcium channel blockers: concomitant administration of beta blockers and calcium channel blockers can induce hypotensive phenomena, bradycardia, conduction abnormalities and make a heart failure condition clinically manifest. Beta-blockers should not be administered in combination with cardiodepressive calcium channel blockers such as verapamil and diltiazem due to additive effects on atrioventricular conduction and ventricular function.
Antiadrenergic agents: The concomitant use of a beta-blocker with antiadrenergic agents, such as reserpine and guanethidine, may result in an excessive reduction of adrenergic tone at rest. Such patients should be carefully monitored to avoid the onset of hypotension and / or marked bradycardia which can evolve into syncopal events.
Insulin and oral hypoglycemic agents: hypoglycemia may occur and the dosage of anti-diabetic drugs may require appropriate adjustments of the dosage. SOTALEX can mask the symptoms of hypoglycemia.
Beta2-Mimetic Agents: Beta-agonist drugs such as salbutamol, terbutaline and isoprenaline may need to be administered at higher doses when used concomitantly with SOTALEX (see Contraindications).
Clonidine: beta-blocking drugs can potentiate hypertension ("rebound" effect) due to the sudden interruption of the administration of clonidine; therefore beta-blockers should be appropriately discontinued a few days before the gradual discontinuation of clonidine.
Tubocurarine-like drugs: the concomitant administration of beta-blocking agents can induce prolongation of neuromuscular block.
Laboratory Tests: The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by photometric methods. Patients with suspected pheochromocytoma, treated with sotalol, must measure urinary metanephrine with alternative diagnostic methods (eg: HPLC with solid phase extraction) to photometry.
Warnings It is important to know that:
Proarrhythmia: The most dangerous adverse event during anti-arrhythmic therapy is the aggravation of pre-existing arrhythmias or the induction of new ones. Drugs that prolong the QT interval can cause torsades de pointes, a polymorphic ventricular tachycardia, associated with prolongation of the QT interval. Our data show that the risk of developing torsades de pointes is associated with prolongation of the QT interval and QTc, decreased heart rate, history of cardiomegaly or heart failure, hypokalaemia and hypomagnesaemia (eg as a consequence of the use of diuretics), high plasma drug concentrations (eg as a result of overdose or renal failure) and interactions of sotalol with other drugs, such as anti- Class I depressants and antiarrhythmics that have been associated with torsades de pointes Women appear to be at increased risk of developing torsades de pointes. The dosage of SOTALEX should be increased with great caution in patients with a prolonged QT interval. An electrocardiographic check performed immediately before or immediately after the episode generally reveals a significant increase in the QT and QTc interval. In clinical studies, SOTALEX was not administered to patients who had a pre-treatment QTc interval greater than 450 msec. Torsades de pointes is a dose-dependent event that usually occurs soon after initiation of therapy or following a dose increase, and which ends spontaneously in most patients. Although most cases of Torsades de Pointes are self-limited, they can be associated with symptoms (eg, syncope) and can progress to ventricular fibrillation. In clinical trials, 4.3% of the 3257 patients with arrhythmias treated showed a new ventricular arrhythmia or worsening of a pre-existing one, including sustained ventricular tachycardia (approximately 1%) and torsades de pointes ( 2.4%). In addition, in about 1% of patients, deaths were considered to be possibly drug related. In the other patients with less severe ventricular and supraventricular arrhythmias, the incidence of torsades de pointes was 1% and 1.4%, respectively.
Severe proarrhythmias, including torsades de pointes, have been shown to be dose dependent, as indicated below:
Other risk factors for torsades de pointes are excessive QTc prolongation and a previous history of cardiomegaly or heart failure. Patients with heart failure and sustained ventricular tachycardia are at higher risk for proarrhythmic events (7%).
Proarrhythmic events may occur not only during the initial phase of therapy but also after each dose increase, generally within 7 days of initiation or increase. A gradual and cautious increase in dosage, starting from 80 mg BID or the dosage identified for each individual patient based on the therapeutic response and the tolerated dose, reduces the risk of proarrhythmia (see Dose, method and time of administration). Therefore, SOTALEX should be administered with caution if the QTc is greater than 500 msec during treatment; in the event that the QTc interval is greater than 550 msec, it must be carefully considered whether to reduce the dose or discontinue therapy. Due to the multifactorial genesis of torsades de pointes, care should be taken, regardless of the duration of the QTc interval.
Sudden discontinuation of treatment: Hypersensitivity to catecholamines has occasionally been observed following discontinuation of beta-blocker therapy as well as worsening anginal symptoms, arrhythmias and rarely myocardial infarction have occasionally been reported. In patients with ischemic heart disease, monitor the patient closely when discontinuing chronically administered SOTALEX therapy. If possible, the dosage should be gradually reduced over a period of 1-2 weeks. Since ischemic heart disease is a common and sometimes not is diagnosed, it may occur that abrupt discontinuation of SOTALEX therapy may reveal latent coronary insufficiency.
Heart failure: beta-blocker may further depress myocardial contractility and induce worsening of heart failure. Caution is advised when initiating therapy in patients with left ventricular dysfunction adequately controlled by therapy (eg. ACE inhibitors, diuretics , digitalis); in this case it is advisable to administer a low initial dose of SOTALEX and gradually increase the dosage. Post recent infarction: in post-infarct patients with left ventricular dysfunction, the risks and benefits associated with the administration of sotalol should be carefully weighed. . Careful monitoring and gradual increase in dosage are of particular importance at the start of and during therapy.Negative results observed in clinical trials with anti-arrhythmic drugs (e.g. apparent excess mortality) suggest that SOTALEX should not be given to patients with left ventricular ejection fraction ≤ 40% without severe ventricular arrhythmias. In a large controlled clinical study in patients with recent myocardial infarction without heart failure, with or without ventricular arrhythmias, the use of sotalol was associated with a non-statistically significant reduction in mortality compared to placebo (18%). 320 mg QD fixed dose post-infarct study and in a further small randomized study in post-infarct patients with LVEF ≤ 40% treated at high doses (640 mg / day), there were indications of an excess of sudden early deaths.
Electrolyte disturbances: SOTALEX should not be used in patients with hypokalaemia or hypomagnesaemia without correcting these changes. These conditions can further prolong the duration of the QT segment and increase the risk of torsades de pointes. Particular attention should be paid to the hydro-electrolyte balance and acid-base balance in patients with severe or prolonged diarrhea or in patients undergoing treatment that facilitates the urinary elimination of magnesium and / or potassium.
Changes in the electrocardiogram: Excessive prolongation of the QT interval (> 550 msec) can be a sign of toxicity and should be avoided. Sinus bradycardia (heart rate
Anaphylaxis: Patients with a history of allergy may have more severe allergic reactions during beta-blocker therapy. Furthermore, such patients may not respond adequately to the doses of adrenaline usually employed as anti-allergic therapy.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Pregnancy
Animal studies have not shown a teratogenic effect or other potentially harmful effects on the fetus. Although there are no adequate and controlled studies in pregnant women, sotalol hydrochloride has been shown to pass the blood-placental barrier and has been found in amniotic fluid. Beta-blocking compounds can reduce placental perfusion, which can lead to fetal death or premature birth. In addition, some adverse effects (hypoglycaemia and bradycardia) may appear in the fetus or neonate. In the newborn, the risk of developing heart and lung complications is increased. Therefore SOTALEX should not be used in pregnancy.
Feeding time
SOTALEX is excreted in the milk of laboratory animals and was found in breast milk. Because of the potential adverse reactions that may occur during breastfeeding, while taking SOTALEX, a decision should be made whether to discontinue breastfeeding or to discontinue therapy, depending on the importance of the drug to the mother.
Effects on ability to drive and use machines: There are no known effects of the treatment on the ability to drive and use machines.
Dosage and method of use How to use Sotalex: Dosage
Initiation of SOTALEX treatment and subsequent dose adjustments should be preceded by appropriate clinical evaluation of the patient, such as measuring the QT interval on the electrocardiogram, renal function and water and electrolyte balance, as well as concomitant intake of other Pharmacological compounds (see Special Warnings and Precautions for Use). As with other antiarrhythmic drugs, heart rhythm should be monitored at the initiation and eventuality of dose increases of SOTALEX therapy.
Dosage should be individualized and based on the patient's response to treatment. Proarrhythmic effects may occur not only at the start of therapy but whenever the dosage is increased. In view of its beta-blocking properties, treatment with SOTALEX should not be stopped abruptly, especially in patients with ischemic heart disease (angina pectoris, previous myocardial infarction). o arterial hypertension, in order to prevent exacerbation of the underlying disease (see Special warnings).
The following dosage schedule is suggested: the initial dose is 80 mg, administered as a single dose or in two divided doses (one administration every 12 hours). The dosage can be gradually increased, maintaining the 2-3 day intervals between each dose increase, in order to allow the achievement of the steady state and the monitoring of the duration of the QT segment.
Some patients with threatening ventricular arrhythmias, refractory to therapy, may require administration of 480-640 mg / day. However, this posology should only be achieved if the benefit outweighs the risk of adverse reactions, particularly torsades de pointes (see Special warnings).
Dosage in renal insufficiency
SOTALEX is mainly excreted via the urine, and therefore the dosage should be reduced when creatinine clearance is <60 ml / min, according to the following scheme:
Creatinine clearance can be extrapolated from serum creatinine value, according to the Cockroft and Gault formula:
Women: ditto x 0.85
Dosage in hepatic insufficiency
No dosage reduction is required in patients with hepatic insufficiency.
Pediatric use
The efficacy and safety of SOTALEX in patients under the age of 18 has not been adequately determined.
Duration of treatment
According to medical prescription
Overdose What to do if you have taken too much Sotalex
Episodes of overdose, whether intentional or accidental, have rarely resulted in death. Hemodialysis can significantly reduce SOTALEX blood levels.
Symptoms and treatment: The most common signs that can arise in the event of an overdose are: bradycardia, heart failure, hypotension, bronchospasm and hypoglycemia. In cases of intentional overdose of SOTALEX of a large entity (2-16 g) the following clinical events may be encountered: hypotension, bradycardia, prolongation of the QT interval, premature ventricular complexes, ventricular tachycardia, torsades de pointes. SOTALEX therapy should be discontinued and the patient closely observed.When required, the following therapeutic interventions are suggested:
Bradycardia: atropine, another anticholinergic compound, a beta-adrenergic agonist or transvenous "cardiac pacing".
Atrioventricular block (II / III degree): transvenous "cardiac pacing". Hypotension: Adrenaline rather than isoproterenol or noradrenaline may be useful, depending on the associated factors.
Bronchospasm: aminophylline or a beta2-adrenergic agonist via aerosol.
Torsade de pointes: electrical cardioversion, transvenous "cardiac pacing", adrenaline and / or magnesium sulfate.
In case of accidental ingestion / intake of an excessive dose of Sotalex, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Sotalex
SOTALEX is generally well tolerated in most patients. The most frequently reported undesirable events are due to its beta-blocking properties. Adverse events are usually transient in nature and rarely require interruption or discontinuation of treatment. These events include: dyspnoea, fatigue, dizziness, headache, fever, excessive bradycardia and / or hypotension. dose reduction Proarrhythmia, including torsades de pointes, is considered to be the most important adverse event (see Special Warnings and Special Precautions for Use).
Arrhythmia
Several clinical studies have been conducted with oral SOTALEX in a total of 3256 patients with cardiac arrhythmias (1363 of whom with sustained ventricular tachycardia). 2451 patients received the drug for at least 2 weeks. The most significant adverse events were torsade de pointes and the onset of new serious ventricular arrhythmias (see Special Warnings) which occurred in the percentages shown in the following table:
Population studied
Overall, treatment interruptions due to adverse events occurred in 18% of patients studied for arrhythmias. The most frequent adverse events leading to discontinuation of SOTALEX therapy were fatigue 4%, bradycardia (<50 bpm) 3%, dyspnoea 3%, proarrhythmic events 2%, asthenia 2% and dizziness 2%.
Adverse events considered drug related, occurring in 1% or more of patients treated with SOTALEX, are listed below:
Cardiovascular system: bradycardia, dyspnoea, chest pain, palpitations, edema, ECG abnormalities, hypotension, proartimia, syncope, heart failure, presyncope.
Dermatological: rash.
Digestive System: nausea / vomiting, diarrhea, dyspepsia, abdominal pain, flatulence.
Musculoskeletal system: cramps.
Nervous System: fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paraesthesia, mood alterations, anxiety.
Urogenital System: sexual dysfunctions.
General: vision and hearing disturbances, taste disturbances and fever.
Compliance with the instructions given in this leaflet reduces the risk of undesirable effects. The patient should inform the doctor or pharmacist of any undesirable effect, even if not described in the package leaflet.
Expiry and Retention
See the expiration date indicated on the package; this date is intended for the product in intact packaging, properly stored.
Warning: do not use the medicine after the expiry date indicated on the package.
No special storage precautions.
Composition and pharmaceutical form
Composition
Each tablet contains:
Active ingredient: 80 mg sotalol hydrochloride
Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, anhydrous colloidal silica, stearic acid, magnesium stearate.
Pharmaceutical form and content by weight
Tablets. Box of 40 tablets of 80 mg of sotalol hydrochloride.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SOTALEX 80 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains
Active ingredient: 80 mg sotalol hydrochloride.
03.0 PHARMACEUTICAL FORM
Tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
SOTALEX is indicated in the prophylaxis of paroxysmal supraventricular tachyarrhythmias, in the maintenance of sinus rhythm after conversion of atrial flutter / fibrillation, in threatening or symptomatic ventricular tachyarrhythmias.
04.2 Posology and method of administration
Initiation of SOTALEX treatment and subsequent dose adjustments should be preceded by appropriate clinical evaluation of the patient, such as measuring the QT interval on the electrocardiogram, renal function and water and electrolyte balance, as well as concomitant intake of other pharmacological compounds (see section 4.4).
As with other antiarrhythmic drugs, heart rhythm should be monitored at the initiation and in the event of dose increases of SOTALEX therapy.
Dosage should be individualized and based on the patient's response to treatment. Proarrhythmic effects may occur not only at the start of therapy but whenever the dosage is increased.
In view of its beta-blocking properties, treatment with SOTALEX should not be stopped abruptly, especially in patients with ischemic heart disease (angina pectoris, previous myocardial infarction) or arterial hypertension, in order to prevent exacerbation of the underlying disease (see section 4.4 ).
The following dosage schedule is suggested: the initial dose is 80 mg, administered as a single dose or in two divided doses (once every 12 hours). The dosage can be gradually increased, maintaining 2-3 day intervals between each dose increase, in order to allow the achievement of the steady state and the monitoring of the duration of the QT segment.
Some patients with threatening ventricular arrhythmias, refractory to therapy, may require administration of 480-640 mg / day. However, this posology should only be achieved if the expected benefit outweighs the risk of adverse reactions, particularly torsades de pointes (see section 4.4).
Dosage in renal insufficiency
SOTALEX is mainly excreted via the urine, and therefore the dosage should be reduced when creatinine clearance is
Creatinine clearance can be extrapolated from serum creatinine value, according to the Cockroft and Gault formula:
Women: ditto x 0.85
Dosage in hepatic insufficiency
No dosage reduction is required in patients with hepatic insufficiency.
Pediatric Use: The efficacy and safety of SOTALEX in patients below 18 years has not been adequately established.
04.3 Contraindications
SOTALEX is contraindicated in patients with:
- Bronchial asthma or chronic obstructive diseases of the respiratory system.
- Hypersensitivity to the active substance or to any of the excipients.
- Cardiogenic shock.
- Anesthesia inducing myocardial depression.
- Symptomatic sinus bradycardia.
- Sinus node syndrome, second and third degree atrioventricular block (unless a pacemaker is installed).
- Uncontrolled heart failure.
- Renal insufficiency (Creatinine clearance
- Long QT syndrome (congenital or acquired).
- Metabolic acidosis.
- Untreated pheochromocytoma.
- Hypotension.
- Raynaud's phenomenon and severe disorders of the peripheral circulation.
04.4 Special warnings and appropriate precautions for use
Proarrhythmia: The most dangerous adverse event during anti-arrhythmic therapy is the aggravation of pre-existing arrhythmias or the induction of new ones. Drugs that prolong the QT interval can cause torsades de pointes, a polymorphic ventricular tachycardia , associated with QT interval prolongation. Available data demonstrate that the risk of developing torsades de pointes is associated with QT interval and QTc prolongation, decreased heart rate, history of cardiomegaly or heart failure, "hypokalaemia and" hypomagnesaemia (eg. as a consequence of the use of diuretics), high plasma concentrations of the drug (eg. resulting from overdose or renal insufficiency) and with interactions of sotalol with other drugs, such as anti- Class I depressants and antiarrhythmics that have been associated with torsades de pointes Women appear to be at increased risk of developing torsades de pointes. The dosage of SOTALEX should be increased with great caution in patients with a prolonged QT interval.
An electrocardiographic check performed immediately before or immediately after the episode generally reveals a significant increase in the QT and QTc interval.
In clinical studies, SOTALEX was not administered to patients who had a pre-treatment QTc interval greater than 450 msec.
Torsades de pointes is a dose-dependent event that usually occurs soon after initiation of therapy or following a dose increase, and which ends spontaneously in most patients.Although most cases of Torsades de Pointes are self-limited, they can be associated with symptoms (eg, syncope) and can progress to ventricular fibrillation.
In clinical trials, 4.3% of the 3257 patients with arrhythmias treated showed a new ventricular arrhythmia or worsening of a pre-existing one, including sustained ventricular tachycardia (approximately 1%) and torsades de pointes ( 2.4%). In addition, in about 1% of patients, deaths were considered to be possibly drug related. In the other patients with less severe ventricular and supraventricular arrhythmias, the incidence of torsades de pointes was 1% and 1.4%, respectively.
Severe proarrhythmias, including torsades de pointes, have been shown to be dose dependent, as indicated below:
Other risk factors for torsades de pointes are excessive QTc prolongation and a previous history of cardiomegaly or heart failure.
Patients with heart failure and sustained ventricular tachycardia are at higher risk for proarrhythmic events (7%).
Proarrhythmic events can occur not only during the initial phase of therapy, but also after each dose increase, generally within 7 days of initiation or increase. A gradual and prudent increase in dosage, starting from 80 mg BID or from the dosage identified for each individual patient on the basis of the therapeutic response and the tolerated dose, reduces the risk of proarrhythmia (see section 4.2). Therefore, SOTALEX should be administered with caution if the QTc segment is greater than 500 msec during treatment; in the event that the QTc interval is greater than 550 msec, it must be carefully considered whether to reduce the dose or discontinue therapy. Due to the multifactorial genesis of torsades de pointes, care should be taken, regardless of the duration of the QTc interval.
Sudden interruption of treatment: hypersensitivity to catecholamines has been observed occasionally following the interruption of beta-blocker therapy as well as cases of aggravation of anginal symptoms, arrhythmias and rarely myocardial infarction have occasionally been reported. Particularly in patients with ischemic heart disease, monitor the patient closely when discontinuing chronically administered SOTALEX therapy. If possible, the dosage should be gradually reduced over a period of 1-2 weeks. Since ischemic heart disease is a common and sometimes is not diagnosed, abrupt discontinuation of SOTALEX therapy may reveal latent coronary insufficiency.
Heart failure: beta-blocker may further depress myocardial contractility and induce worsening of heart failure. Caution is advised when initiating therapy in patients with left ventricular dysfunction adequately controlled by therapy (eg: ACE inhibitors, diuretics, digitalis); in this case it is advisable to administer a low initial dose of SOTALEX and gradually increase the dose.
Recent post heart attack: The risks and benefits associated with the administration of sotalol should be carefully weighed in post-infarct patients with left ventricular dysfunction. At the beginning of therapy and during it, careful monitoring and gradual increase in dosage are of particular importance. Negative results observed in clinical trials with anti-arrhythmic drugs (e.g. apparent excess mortality) suggest that SOTALEX should not be administered in patients with left ventricular ejection fraction ≤ 40% who do not have severe ventricular arrhythmias.
In a large controlled clinical study in patients with recent myocardial infarction without heart failure, with or without ventricular arrhythmias, the use of sotalol was associated with a non-statistically significant reduction in mortality compared to placebo (18%). 320 mg QD fixed dose post-heart attack study and in a further small randomized study in post-heart attack patients with LVEF ≤ 40% treated at high doses (640 mg / day), there were indications of an excess of sudden early deaths .
Electrolyte disturbances: SOTALEX should not be used in patients with hypokalaemia or hypomagnesaemia without correcting these changes. These conditions can further prolong the duration of the QT segment and increase the risk of torsades de pointes. Particular attention should be paid to the hydro-electrolyte balance and acid-base balance in patients with severe or prolonged diarrhea or in patients undergoing treatment that facilitates the urinary elimination of magnesium and / or potassium.
Changes in the electrocardiogram: Excessive prolongation of the QT interval (> 550 msec) can be a sign of toxicity and should be avoided. Sinus bradycardia (heart rate
Anaphylaxis: Patients with a history of allergy may have more severe allergic reactions during beta-blocker therapy. Furthermore, such patients may not respond adequately to the doses of adrenaline usually employed as anti-allergic therapy.
Anesthesia: in the course of surgical interventions conducted with myocardial depressive anesthetics (eg: cyclopropane, trichlorethylene) it is necessary to administer beta-blocking drugs with caution.
Diabetes mellitus: In patients with diabetes mellitus (especially if not well compensated) or with previous episodes of spontaneous hypoglycaemia, SOTALEX should be administered with caution as beta-blockers may mask some important warning signs of hypoglycemia (e.g. tachycardia).
Thyrotoxicosis: the beta-blocker may mask some clinical signs (e.g. tachycardia) of hyperthyroidism. Patients with suspected hyperthyroidism should avoid abrupt discontinuation of therapy, which may be followed by worsening of symptoms, including thyrotoxic storm.
Hepatic dysfunction: patients with impaired liver function do not show reductions in elimination of SOTALEX, since the drug is not subject to the phenomenon of first pass metabolism.
Renal dysfunction: SOTALEX is eliminated primarily via the kidney, via glomerular filtration and minimally by tubular secretion. There is a direct correlation between renal function, assessed on the basis of serum creatinine and / or creatinine clearance, and the elimination half-life of SOTALEX. For dosage adjustments to be adopted in the course of renal dysfunction, see section 4.2.
Psoriasis: Beta-blockers have rarely been reported to induce worsening of the symptoms of Psoriasis Vulgaris.
04.5 Interactions with other medicinal products and other forms of interaction
Antiarrhythmics: Class Ia antiarrhythmic drugs (e.g. diisopyramide, quinidine and procainamide) and Class III drugs (e.g. amiodarone) are not recommended as concomitant therapy with SOTALEX due to their ability to prolong the refractory period (see par. 4.4 Co-administration of other beta-blockers with SOTALEX may result in an additive Class II effect.
Potassium depleting diuretics: these drugs can induce hypokalaemia or hypomagnesaemia, increasing the risk of torsades de pointes (see section 4.4).
Potassium depleting drugs: IV amphotericin B, systemic corticosteroids, and some laxative compounds, can induce hypokalaemia; blood potassium levels should be monitored and possibly corrected while using SOTALEX.
Drugs that prolong the QT interval: SOTALEX should be administered with extreme caution together with other drugs that prolong the QT interval such as Class I antiarrhythmics, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, and some quinolone antibiotics (see section 4.4).
Digoxin: Single and multiple doses of SOTALEX do not significantly change digoxin levels. Proarrhythmic events are more frequent in patients treated simultaneously with sotalol and digoxin; however this may be justified, in patients receiving digoxin, by the presence of heart failure, a known risk factor for proarrhythmic events.
Calcium channel blockers: concomitant administration of beta-blockers and calcium channel blockers can induce hypotensive phenomena, bradycardia, conduction abnormalities and heart failure. Beta-blockers should not be administered in combination with cardiodepressive calcium channel blockers such as verapamil and diltiazem due to additive effects on atrioventricular conduction and ventricular function.
Antiadrenergic agents: The concomitant use of a beta-blocker with antiadrenergic agents, such as reserpine and guanethidine, may result in an excessive reduction in resting adrenergic tone. Such patients should be monitored closely to avoid the onset of hypotension and / or marked bradycardia which can evolve into syncopal events.
Oral hypoglycemic insulin: Hypoglycaemia may occur and the dosage of anti-diabetic drugs may require appropriate dosage adjustments. SOTALEX can mask the symptoms of hypoglycemia.
Beta2-Mimetic Agents: beta-agonist drugs such as salbutamol, terbutaline and isoprenaline may need to be administered at higher doses when used concomitantly with SOTALEX (see section 4.3).
Clonidine: beta-blocking drugs can potentiate hypertension ("rebound" effect) due to the sudden interruption of the administration of clonidine; therefore beta-blockers should be appropriately discontinued a few days before the gradual discontinuation of clonidine.
Tubocurarine-like drugs: the concomitant administration of beta-blocking agents can induce prolongation of neuromuscular block.
Laboratory Tests: The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by photometric methods. Patients with suspected pheochromocytoma, treated with sotalol, must measure urinary metanephrine with alternative diagnostic methods (eg: HPLC with solid phase extraction) to photometry.
04.6 Pregnancy and lactation
Pregnancy: Animal studies have not shown a teratogenic effect or other potentially harmful effects on the fetus. Although there are no adequate and controlled studies in pregnant women, sotalol hydrochloride has been shown to pass the blood-placental barrier and has been found in amniotic fluid. Beta-blocking compounds can reduce placental perfusion, which can lead to fetal death or premature birth.
In addition, some adverse reactions (hypoglycaemia and bradycardia) may appear in the fetus or neonate. In the newborn, the risk of developing heart and lung complications is increased. Therefore SOTALEX should be used during pregnancy only in case of real need and in any case when the benefit of the treatment is considered to be greater than the risk to the fetus. In these cases, the newborn should be monitored very closely for 48-72 hours after birth, if it was not possible to stop treatment in the mother 2-3 days before delivery.
Lactation: SOTALEX is excreted in the milk of laboratory animals and was found in breast milk. Because of the potential adverse reactions that may occur during breastfeeding, a decision should be made whether to discontinue breastfeeding or discontinue therapy while taking SOTALEX, depending on the importance of the drug to the mother.
04.7 Effects on ability to drive and use machines
Not relevant.
04.8 Undesirable effects
The most frequently reported undesirable events are due to its beta-blocking properties. Adverse events are usually transient in nature and rarely require interruption or discontinuation of treatment. These events include: dyspnoea, fatigue, dizziness, headache, fever, excessive bradycardia and / or hypotension. If they occur, these side effects usually disappear with dose reduction. Proarrhythmia, including torsades de pointes, is considered to be the most important adverse event (see section 4.4).
Arrhythmia
Several clinical studies have been conducted with oral SOTALEX in a total of 3256 patients with cardiac arrhythmias (1363 of whom with sustained ventricular tachycardia). 2451 patients received the drug for at least 2 weeks. The most significant adverse events were torsade de pointes and the onset of new serious ventricular arrhythmias (see section 4.4) which occurred in the percentages reported in the following table:
Population studied
Overall, treatment interruptions due to adverse events occurred in 18% of patients studied for arrhythmias. The adverse events that most frequently led to discontinuation of SOTALEX therapy were: fatigue 4%, bradycardia (asthenia 2% and dizziness 2%.
Adverse events considered drug related, occurring in 1% or more of patients treated with SOTALEX are listed below:
Cardiovascular system: bradycardia, dyspnoea, chest pain, palpitations, edema, ECG abnormalities, hypotension, proartimia, syncope, heart failure, presyncope.
Dermatological: rash.
Digestive system: nausea / vomiting, diarrhea, dyspepsia, abdominal pain, flatulence.
Musculoskeletal system: cramps.
Nervous system: fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paraesthesia, mood alterations, anxiety.
Urogenital apparatus: sexual dysfunctions.
General: impaired vision and hearing, altered taste and fever.
04.9 Overdose
Episodes of overdose, whether intentional or accidental, have rarely resulted in death. Hemodialysis can significantly reduce SOTALEX blood levels.
Symptoms and treatment: The most common signs that can arise in case of overdose are: bradycardia, heart failure, hypotension, bronchospasm and hypoglycaemia. In cases of intentional overdose of SOTALEX of a large entity (2-16 g) the following clinical events may be encountered: hypotension, bradycardia, prolongation of the QT interval, premature ventricular complexes, ventricular tachycardia, torsades de pointes. SOTALEX therapy should be discontinued and the patient closely observed.When required, the following therapeutic interventions are suggested:
Bradycardia: atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous "cardiac pacing".
Atrioventricular block (II-III degree): transvenous "cardiac pacing".
Hypotension: Adrenaline rather than isoproterenol or norepinephrine may be useful, depending on the associated factors.
Bronchospasm: aminophylline or a beta2-adrenergic agonist via aerosol.
Torsade de pointes: electrical cardioversion, transvenous "cardiac pacing", adrenaline and / or magnesium sulfate.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: non-selective, non-associated beta-blockers.
ATC code: C07AA07.
Mechanism of action. SOTALEX (sotalol hydrochloride) is a non-selective blocking agent of beta1 and beta2 adrenergic receptors, lacking intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (ASM). Like other beta-blockers, SOTALEX inhibits the increase of renin. After administration of SOTALEX, a significant renin-suppressive effect has been documented both at rest and during exercise.
Its beta-blocking activity induces a reduction in heart rate and a limited reduction in myocardial contractility. These changes reduce oxygen consumption and heart work.
SOTALEX has antiarrhythmic properties typical of both beta-blockers (Vaughan-Williams Class II) and antiarrhythmic drugs (Vaughan-Williams Class III), which consist in prolonging the duration of the action potential of myocardial cells.
SOTALEX has no known effects on the rapid deflection phase of the action potential (depolarization phase). SOTALEX uniformly prolongs the duration of the myocardial action potential by delaying only the repolarization phase. The main effects consist in the prolongation of the action potential at the level of the atrial myocardium, the ventricular myocardium and the accessory conduction pathways.
Class II and III antiarrhythmic properties can be highlighted on the ECG trace by lengthening the PR, QT and QTc intervals (QT corrected for heart rate).
The right and left-handed isomers of sotalol hydrochloride have antiarrhythmic effects attributable to Vaughan-Williams Class III, while the beta-blocking activity is due to the left-handed isomer. Although significant beta-blockade can already be found at daily doses of 25 mg, it is necessary to increase to daily doses of over 160 mg to appreciate the Class III antiarrhythmic effects.
05.2 "Pharmacokinetic properties
After oral administration, the bioavailability of SOTALEX is greater than 90%, the maximum plasma concentration is reached between 2.5 and 4 hours, while the steady state is achieved in about 2-3 days. Absorption is reduced by approximately 20% when SOTALEX is administered concomitantly with a normal meal.
In the dose range of 40-640 mg / day, SOTALEX exhibits linear kinetics, the blood concentration being proportional to the dose administered orally.
Distribution of SOTALEX occurs in the central (plasma) and peripheral compartments, where the elimination half-life is 10-20 hours. SOTALEX does not bind to plasma proteins and is not metabolised. Finally, there is minimal variability between the different ones. subjects in the plasma levels of the drug.
The pharmacokinetics of the dextro- and left-handed isomers of sotalol are comparable. SOTALEX crosses the blood-brain barrier in a very limited manner, being found in concentrations of 10% in the cerebrospinal fluid compared to those in plasma. The major route of elimination is via the kidney. Approximately 80% -90% of the dose is excreted unchanged in the urine, while the remaining drug is excreted in the faeces. In case of renal insufficiency appropriate dose reductions are necessary (see section 4.4).
Age does not significantly alter the pharmacokinetics of SOTALEX, although in cases of renal dysfunction in the elderly there may be a reduction in the level of drug excretion and consequent pharmacological accumulation.
Hemodynamic properties. In men, SOTALEX produces significant reductions in heart rate and output, without alterations in stroke volume. heart rate by 21-24% while systolic and diastolic blood pressure were reduced by about 8%.
Exercise or isoproterenol-induced tachycardia is neutralized by SOTALEX, while peripheral resistance is slightly increased in some patients. SOTALEX does not significantly change systemic and pulmonary arterial pressure in normotensive subjects. In hypertensive patients, SOTALEX produces marked reductions in both systolic and diastolic blood pressure. Although SOTALEX is normally well tolerated, special care should be taken in patients with reduced cardiac reserve as deterioration of ventricular function may occur.
Electrophysiological properties. In humans, the Class II (beta-blocking) electrophysiological effects of SOTALEX are manifested by an increase in the duration of the sinus node cycle (slow heartbeat), a reduction in conduction at the level of the atrioventricular node and an increase in refractory period of the atrioventricular node. The electrophysiological effects of Class III consist in the prolongation of the monophasic atrial and ventricular action potential, in the prolongation of the effective refractory period of the ventricular myocardium and of the accessory atrioventricular conduction pathways (if present), both antegrade and retrograde. After oral administration of doses between 160 and 640 mg / day, a mean dose-dependent increase in QT duration of 40-100 msec and 10-40 msec in QTc is shown on the ECG (see section 4.4). No significant changes in the QRS interval are found.
Clinical Studies. The Electrophysiologic Study Versus Electrographic Monitoring (ESVEM) study was designed to compare two different criteria for choosing antiarrhythmic therapy (Electrophysiological Study - SEF - vs. Holter dynamic ECG monitoring) in patients with a history of sustained ventricular tachycardia (TVS ) or ventricular fibrillation (VF), in which VTV / VF were also inducible through the PES and at least 10 or more premature ventricular contractions / hour were found on Holter. The acute overall therapeutic response, assessed limited to the first randomized drug in the study, was 39% for sotalol compared to 30% for the other drugs. When the response to therapy was evaluated based on its ability to suppress arrhythmias induced by the electrophysiological test, sotalol showed a response of 36% compared to the 13% reported by all other drugs. Using the reduction of arrhythmias as a criterion for pharmacological efficacy. highlighted during the Holter, sotalol produced a response rate of 41% compared to 45% of the other drugs. Among patients who responded acutely, and who were maintained on long-term therapy, sotalol demonstrated better survival during the 2-year follow-up than the other comparators (Mortality = 13% vs 22%). In the same period, a lower incidence of VT (30% vs 60%) and a lower frequency of treatment interruptions (38% vs 75-80%) were also highlighted for the group treated with sotalol. The most commonly used sotalol dose was 320-480 mg / day (66% of patients), while 16% of patients received a dose ≤ 240 mg / day and 18% a dose ≥ 640 mg / day.
05.3 Preclinical safety data
Carcinogenesis, mutagenesis, reproduction
No signs of carcinogenic activity were observed both in rats treated for 24 months with oral doses of sotalol about 30 times (137-275 mg / kg / day) higher than those recommended in humans, and in mice treated for 24 months with doses approximately 450/750 times higher (4141/7122 mg / kg / day) at the therapeutic dose. There was also no significant reduction in the fertility of rats treated with oral doses of 1000 mg / kg / day (approximately 100 times the maximum recommended in humans) before mating, except for a small reduction in the number of offspring. .
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate, microcrystalline cellulose, corn starch, anhydrous colloidal silica, stearic acid, magnesium stearate.
06.2 Incompatibility
None known.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
No special storage precautions.
06.5 Nature of the immediate packaging and contents of the package
Blister 40 tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
BRISTOL-MYERS SQUIBB S.r.l. - Via Virgilio Maroso, 50 - Rome
08.0 MARKETING AUTHORIZATION NUMBER
Sotalex 80 mg tablets - 40 tablets A.I.C. N ° 023245020.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
May 2010.
10.0 DATE OF REVISION OF THE TEXT
August 2011
