Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Neon Healthcare Limited, Mill Studio Business Centre, Crane Mead, Ware, Hertfordshire, SG12 9PY, United Kingdom
Sotacor should not be used where there is evidence of sick sinus syndrome; second and third degree AV heart block unless a functioning pacemaker is present; congenital or acquired long QT syndromes; torsades de pointes; symptomatic sinus bradycardia; uncontrolled congestive heart failure; cardiogenic shock; anaesthesia that produces myocardial depression; untreated phaeochromocytoma; hypotension (except due to arrhythmia); Raynaud’s phenomenon and severe peripheral circulatory disturbances; history of chronic obstructive airway disease or bronchial asthma; hypersensitivity to any of the components of the formulation; metabolic acidosis; renal failure (creatinine clearance <10 ml/min).
Hypersensitivity to catecholamines is observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias, and in some cases, myocardial infarction have been reported after abrupt discontinuation of beta-blocker therapy. Patients should be carefully monitored when discontinuing chronically administered Sotacor, particularly those with ischaemic heart disease. If possible the dosage should be gradually reduced over a period of one to two weeks. Because coronary artery disease is common and may be unrecognised in patients receiving Sotacor, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency. In addition, hypertension may develop.
The most dangerous adverse effect of Class I and Class III antiarrhythmic drugs (such as sotalol) is the aggravation of pre- existing arrhythmias or the provocation of new arrhythmias. Drugs that prolong the QT-interval may cause torsades de pointes, a polymorphic ventricular tachycardia associated with prolongation of the QT-interval. Experience to date indicates that the risk of torsades de pointes is associated with the prolongation of the QT-interval, reduction of the heart rate, reduction in serum potassium and magnesium high plasma sotalol concentrations and with the concomitant use of sotalol and other medications which have been associated with torsades de pointes (see section 4.5). Females may be at increased risk of developing torsades de pointes.
The incidence of torsades de pointes is dose dependent. Torsades de pointes usually occurs within 7 days of initiating therapy or escalation of the dose and can progress to ventricular fibrillation.
In clinical trials of patients with sustained VT/VF the incidence of severe proarrhythmia (torsades de pointes or new sustained VT/VF) was <2% at doses up to 320mg. The incidence more than doubled at higher doses.
Other risk factors for torsades de pointes were excessive prolongation of the QTC and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure have the highest risk of serious proarrhythmia (7%).
Proarrhythmic events must be anticipated not only on initiating therapy but with every upward dose adjustment. Initiating therapy at 80mg with gradual upward dose titration thereafter reduces the risk of proarrhythmia. In patients already receiving Sotacor should be used with caution if the QTC exceeds 500 msec whilst on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when the QTC-interval exceeds 550 msec. Due to the multiple risk factors associated with torsades de pointes, however, caution should be exercised regardless of the QTC-interval.
Sotacor should not be used in patients with hypokalaemia or hypomagnesaemia prior to correction of imbalance; these conditions can exaggerate the degree of QT prolongation, and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhoea or patients receiving concomitant magnesium- and/or potassium-depleting drugs.
Beta-blockade may further depress myocardial contractility and precipitate more severe heart failure. Caution is advised when initiating therapy in patients with left ventricular dysfunction controlled by therapy (i.e. ACE Inhibitors, diuretics, digitalis, etc); a low initial dose and careful dose titration is appropriate.
In post-infarction patients with impaired left ventricular function, the risk versus benefit of sotalol administration must be considered. Careful monitoring and dose titration are critical during initiation and follow-up of therapy. The adverse results of clinical trials involving antiarrhythmic drugs (i.e. apparent increase in mortality) suggest that Sotacor should be avoided in patients with left ventricular ejection fractions ≤40% without serious ventricular arrhythmias.
Excessive prolongation of the QT- interval, >500 msec, can be a sign of toxicity and should be avoided (see Proarrhythmias above). Sinus bradycardia has been observed very commonly in arrhythmia patients receiving sotalol in clinical trials. Bradycardia increases the risk of torsades de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.
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.
As with other beta-blocking agents, Sotacor should be used with caution in patients undergoing surgery and in association with anaesthetics that cause myocardial depression, such as cyclopropane or trichloroethylene.
Sotacor should be used with caution in patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycaemia, since beta-blockade may mask some important signs of the onset of acute hypoglycaemia, e.g. tachycardia.
Beta-blockade may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.
As sotalol is mainly eliminated via the kidneys the dose should be adjusted in patients with renal impairment (see section 4.2).
Beta-blocking drugs have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.
This product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III antiarrhythmic drugs such as amiodarone and bepridil are not recommended as concomitant therapy with Sotacor, because of their potential to prolong refractoriness (see section 4.4). The concomitant use of other beta-blocking agents with Sotacor may result in additive Class II effects.
Sotacor should be given with extreme caution in conjunction with other drugs known to prolong the QT-interval such as phenothiazines, tricyclic antidepressants, terfenadine and astemizole. Other drugs that have been associated with an increased risk for torsades de pointes include erythromycin IV, halofantrine, pentamidine, and quinolone antibiotics.
Beta-adrenergic blocking agents may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by floctafenine.
Concurrent administration of beta- blocking agents and calcium channel blockers has resulted in hypotension, bradycardia, conduction defects, and cardiac failure. Beta- blockers should be avoided in combination with cardiodepressant calcium-channel blockers such as verapamil and diltiazem because of the additive effects on atrioventricular conduction, and ventricular function.
Hypokalaemia or hypomagnesaemia may occur, increasing the potential for torsade de pointes (see section 4.4).
Amphotericin B (IV route), corticosteroids (systemic administration), and some laxatives may also be associated with hypokalaemia. Potassium levels should be monitored and corrected appropriately during concomitant administration with Sotacor.
Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, the beta-blocker should be discontinued slowly several days before the gradual withdrawal of clonidine.
Single and multiple doses of Sotacor do not significantly affect serum digoxin levels. Proarrhythmic events were more common in sotalol treated patients also receiving digitalis glycosides; however, this may be related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digitalis glycosides. Association of digitalis glycosides with beta-blockers may increase auriculo-ventricular conduction time.
Concomitant use of catecholamine- depleting drugs, such as reserpine, guanethidine, or alpha methyldopa, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients should be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope.
Hyperglycaemia may occur, and the dosage of antidiabetic drugs may require adjustment. Symptoms of hypoglycaemia (tachycardia) may be masked by beta-blocking agents.
The neuromuscular blockade is prolonged by beta-blocking agents.
Patients in need of beta-agonists should not normally receive Sotacor. However, if concomitant therapy is necessary beta-agonists may have to be administered in increased dosages.
The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by photometric methods. Patients suspected of having phaeochromocytoma and who are treated with sotalol should have their urine screened utilizing the HPLC assay with solid phase extraction.
Animal studies with sotalol hydrochloride have shown no evidence of teratogenicity or other harmful effects on the foetus. Although there are no adequate and well-controlled studies in pregnant women, sotalol hydrochloride has been shown to cross the placenta and is found in amniotic fluid. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Therefore, Sotacor should be used in pregnancy only if the potential benefits outweigh the possible risk to the foetus. The neonate should be monitored very carefully for 48-72 hours after delivery if it was not possible to interrupt maternal therapy with Sotacor 2-3 days before the birthdate.
Most beta-blockers, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended during administration of these compounds.
There are no data available, but the occasional occurrence of side-effects such as dizziness and fatigue should be taken into account (see section 4.8 Undesirable effects).
Sotacor is well tolerated in the majority of patients, with the most frequent adverse effects arising from its beta-blockade properties. Adverse effects are usually transient in nature and rarely necessitate interruption of, or withdrawal from treatment. These include dyspnea, fatigue, dizziness, headache, fever, excessive bradycardia and/or hypotension. If they do occur, they usually disappear when the dosage is reduced. The most significant adverse effects, however, are those due to proarrhythmia, including torsades de pointes (see section 4.4).
Frequency is defined using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000) including isolated reports.
The following are adverse events considered related to therapy with Sotacor:
| System Organ Class | Common |
|---|---|
| Cardiac disorders | Bradycardia Dyspnoea Chest pain Palpitations Oedema Electrocardiogram abnormal Hypotension Arrhythmia Syncope Presyncope Cardiac failure |
| Skin and subcutaneous tissue disorder | Rash |
| Gastrointestinal disorder | Nausea Vomiting Diarrhoea Dyspepsia Abdominal pain Flatulence |
| Musculoskeletal, connective tissue and bone disorders | Muscle spasms |
| Nervous system disorders | Headache Dizziness Fatigue Asthenia Lightheadedness Paraesthesia Dysgeusia |
| Psychiatric disorders | Sleep disorder Mood altered Depression Anxiety |
| Reproductive system and breast disorders | Sexual dysfunction |
| Eye disorders | Visual disturbance |
| Ear and labyrinth disorders | Hearing disturbances |
| General disorders and administration site conditions | Pyrexia |
In clinical trials, 3256 patients with cardiac arrhythmias (1363 with sustained ventricular tachycardia) received oral Sotacor, of whom 2451 received the drug for at least two weeks. The most significant adverse events were torsade de pointes and other serious new ventricular arrhythmias (see section 4.4), which occurred at the following rates:
| Patient Populations | |||
|---|---|---|---|
| VT/VF (n=1,363) | NSVT/PVC (n=946) | SVA (n=947) | |
| Torsade de Pointes | 4.1% | 1.0% | 1.4% |
| Sustained VT/VF | 1.2% | 0.7% | 0.3% |
VT = ventricular tachycardia; VF = ventricular fibrillation; NSVT = nonsustained ventricular tachycardia; PVC = premature ventricular contraction; SVA = supraventricular arrhythmia.
Overall, discontinuation because of unacceptable adverse events was necessary in 18% of all patients in cardiac arrhythmia trials. The most common adverse events leading to discontinuation of Sotacor are listed in the table below:
| - fatigue | 4% |
| - bradycardia(<50 bpm) | 3% |
| - dyspnoea | 3% |
| - proarrythmia | 2% |
| - asthenia | 2% |
| - dizziness | 2% |
Cold and cyanotic extremities, Raynaud’s phenomenon, increase in existing intermittent claudication and dry eyes have been seen in association with other beta-blockers.
Not applicable.
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