Toxicity:
Individual response varies greatly, death in adults has followed ingestion of about 2 g, and ingestion of more than 40 mg may cause serious problems in children.
Symptoms:
Cardiac - Bradycardia, hypotension, pulmonary oedema, syncope and cardiogenic shock may develop. Conduction abnormalities such as first or second degree AV block may occur. Rarely arrhythmias may occur. Development of cardiovascular complications is more likely if other cardioactive drugs, especially calcium channel blockers, digoxin cyclic antidepressants or neuroleptics have also been ingested. The elderly and those with underlying ischaemic heart disease are at risk of developing severe cardiovascular compromise.
CNS -Drowsiness, confusion, seizures, hallucinations, dilated pupils and in severe cases coma may occur. Neurological signs such as coma or absence of pupil reactivity are unreliable prognostic indicators during resuscitation.
Other features - bronchospasm, vomiting and occasionally CNS-mediated respiratory depression may occur. The concept of cardioselectivity is much less applicable in the overdose situation and systemic effects of beta-blockade include bronchospasm and cyanosis. Particularly in those with pre-existing airways disease. Hypoglycaemia and hypocalcaemia are rare and occasionally generalised spasm may also be present.
Treatment:
In cases of overdose or extreme falls in the heart rate or blood pressure, treatment with Obsidan must be stopped. In addition to primary poison elimination measures, vital parameters must be monitored and corrected accordingly in intensive care. In case of cardiac arrest, the resuscitation of several hours may be indicated.
This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal (50 g for adults, 1 g/kg for children) if an adult presents within 1 hour of ingestion of more than a therapeutic dose or a child for any amount. Atropin should be administrated before gastric lavage, when required as there is a risk of vagal stimulation. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.
Excessive bradycardia may respond to large doses of atropine (3 mg intravenously for an adult and 0.04 mg/kg for a child) and/or a cardiac pacemaker.
For severe hypotension, heart failure or cardiogenic shock in adults a 5-10mg IV bolus of glucagon (50-150 micrograms/kg in a child) should be administered over 10 minutes to reduce the likelihood of vomiting, followed by an infusion of 1-5 mg/hour (50 micrograms/kg/hour), titrated to clinical response. If glucagon is not available or if there is severe bradycardia and hypotension, which is not improved by glucagon, the beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, dopamine or noradrenalin. In severe hypotension additional inotropic support may be necessary with a beta agonist such as dobutamine 2.5-40 micrograms/kg/min (adults and children). It is likely that these doses would be inadequate to reverse the cardiac effects of beta blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.
Nebulised salbutamol 2.5-5 mg should be given for bronchospasm. Intravenous aminophylline may be of benefit in severe cases (5 mg/kg over 30 mins followed by an infusion of 0.5-1 mg/kg/hour). Do not give the initial loading dose of 5 mg/kg if the patient is taking oral theophylline or aminophylline.
Cardiac pacing may also be effective at increasing heart rate but does not always correct hypotension secondary to myocardial depression.
In cases of generalised spasm, a slow intravenous dose of diazepam may be used (0.1-0.3 mg/kg body weight).
- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.
- Cardiac decompensation which is not adequately treated.
- Sick sinus syndrome/SA-block.
- History of bronchospasm or bronchial asthma, chronic obstructive pulmonary disease.
- Metabolic acidosis.
- Second and third-degree heart block.
- Patients prone to hypoglycaemia, e.g. due to prolonged fasting or restricted counter regulatory reserve.
- Cardiogenic shock.
- Untreated phaeochromocytoma.
- Severe bradycardia.
- Severe hypotension
- Severe peripheral arterial disturbances
- Prinzmetal's angina
Not applicable
Obsidan is usually well tolerated. In clinical studies the undesired events reported are usually attributable to the pharmacological actions of Obsidan.
Adverse reactions related to Obsidan are listed below by system organ class and frequency. Frequencies are defined as:
Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be estimated from the available data).
| System Organ Class | Common | Uncommon | Rare | Very Rare | Not known |
| Blood and lymphatic system disorders | Thrombocytopaenia | Agranulocytosis | |||
| Immune system disorders | Angioedema | ||||
| Metabolism and nutrition disorders | Hypoglycaemia in neonates, infants, children, elderly patients, patients on haemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and patients with chronic liver disease has been reported. Changes in lipid metabolism(changes in blood concentrations of triglycerides and cholesterol). Severe hypoglycemia may rarely lead to seizures or coma. | ||||
| Psychiatric disorders | Sleep disturbances, nightmares | Hallucinations, psychoses, mood changes | Depression | ||
| Nervous system disorders | Confusion, memory loss, paraesthesia, dizziness | Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported | Headache, seizure linked to hypoglycaemia | ||
| Eye disorders | Dry eyes, visual disturbances | Conjunctivitis | |||
| Cardiac disorders | Bradycardia, cold extremities | Heart failure deterioration, precipitation of heart block, postural hypotension, which may be associated with syncope | Worsening of attacks of angina pectoris | ||
| Vascular disorders | Raynaud's phenomenon | Exacerbation of intermittent claudication | |||
| Respiratory, thoracic and mediastinal disorders | Breathlessness | Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome | Dyspnoea | ||
| Gastrointestinal disorders | Gastrointestinal disturbance, such as nausea, vomiting, diarrhoea | Constipation, dry mouth | |||
| Skin and subcutaneous tissue disorders | Purpura, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes | Isolated cases of hyperhidrosis has been reported | |||
| Musculoskeletal and connective tissue disorders | Arthralgia | ||||
| Renal and urinary disorders | Reduced renal blood flow and GFR | ||||
| Reproductive system and breast disorders | Impotence | ||||
| General disorders and administration site conditions | Fatigue and/or lassitude (often transient) | Dizziness | |||
| Investigations | An increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear |
Discontinuance of the drug should be considered if, according to clinical judgement, the wellbeing of the patient is adversely affected by any of the above reactions. Cessation of therapy with a beta-blocker should be gradual. In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, local tolerance, genotoxicity, carcinogenic potential and toxicity to reproduction.
- Angina pectoris.
- Hypertension.
- Long-term prophylaxis against myocardial reinfarction after recovery from acute myocardial infarction
- Hypertrophic obstructive cardiomyopathy.
- Essential tremor.
- Supraventricular cardiac arrhythmia.
- Ventricular cardiac arrythmias.
- Hyperthyroidism and thyrotoxicosis
- Phaeochromocytoma (with an alpha-blocker).
- Migraine.
- Prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices.
Pharmacotherapeutic group: Beta blocking agents, non-selective (beta blocker) ATC code: C07AA05
Obsidan is a competitive antagonist at both the beta1- and beta2 adrenoceptors. It has no agonist activity at the beta adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1 to 3 mg/litre, though such concentrations are rarely achieved during oral therapy.
Competitive beta blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta agonists such as isoprenaline.
Obsidan as with other beta-blockers, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.
Obsidan is a racemic mixture and the active form is the S (-) isomer of Obsidan. With the exception of inhibition of the conversion of thyroxine to triiodothyronine, it is unlikely that any additional ancillary properties possessed by R (+) Obsidan, in comparison with the racemic mixture, will give rise to different therapeutic effects.
Obsidan is effective and well tolerated in most ethnic populations, although the response may be less in black patients.
Following intravenous administration the plasma half-life of Obsidan is about 2 hours and the ratio of metabolites to parent drug in the blood is lower than after oral administration. In particular 4-hydroxyObsidan is not present after intravenous administration. Obsidan is completely absorbed after oral administration and peak plasma concentrations occur 1 to 2 hours after dosing in fasting patients. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Obsidan is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Obsidan is highly protein bound (80 to 95%).
Obsidan as with other beta-blockers:
- although contraindicated in uncontrolled heart failure , may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.
- should not be used in combination with calcium channel blockers with negative inotropic effects (e.g. verapamil, diltiazem), as it can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
- although contraindicated in severe peripheral arterial circulatory disturbances , may also aggravate less severe peripheral arterial circulatory disturbances.
- due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.
- may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Obsidan occasionally causes hypoglycaemia, even in non-diabetic patients, e.g. neonates, infants, children, elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with Obsidan has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of Obsidan and hypoglycaemic therapy in diabetic patients. Obsidan may prolong the hypoglycaemic response to insulin.
- may mask the signs of thyrotoxicosis.
- should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.
- will reduce heart rate as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced.
- may cause a more severe reaction to a variety of allergens when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.
Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days. Patients should be followed during withdrawal especially those with ischaemic heart disease.
When a patient is scheduled for surgery and a decision is made to discontinue beta-blocker therapy, this should be done at least 48 hours prior to the procedure. The risk/benefit of stopping beta blockade should be made for each patient.
Since the half-life may be increased in patients with significant hepatic or renal impairment, caution must be exercised when starting treatment and selecting the initial dose.
Obsidan must be used with caution in patients with decompensated cirrhosis. In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with Obsidan may increase the risk of developing hepatic encephalopathy.
In patients with chronic obstructive pulmonary disease, non-selective beta blockers such as Obsidan may aggravate the obstructive condition. Therefore Obsidan should not be used in this condition.
Bronchospasm can usually be reversed by beta2 agonist bronchodilators such as salbutamol. Large doses of the beta bronchodilator may be required to overcome the beta blockade produced by Obsidan and the dose should be titrated according to the clinical response; both intravenous and inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2 mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.
Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported in patients administered Obsidan.
Interference with laboratory tests:
Obsidan has been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.
Lactose:
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Obsidan has no or negligible influence on the ability to drive and use machines. It should be taken into account that occasionally dizziness or fatigue may occur.
Adults:
Hypertension
Initially 40 mg two or three times daily, which may be increased by 80 mg per day at weekly intervals according to response. The usual dose range is 160 to 320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
Angina, migraine and essential tremor
The starting dose is 40 mg two to three times daily, increasing by the same amount at weekly intervals according to the patient response. An adequate response in migraine is usually seen in the range 80 to 160 mg/day and in angina and essential tremor in the range 120 to 240 mg/day.
Arrhythmias, hypertrophic obstructive cardiomyopathy and thyrotoxicosis
A dosage range of 10 to 40 mg three or four times a day usually achieves the required response.
Post myocardial infarction
Treatment should start between days 5 and 21 after myocardial infarction, with an initial dose of 40mg four times a day for two or three days. In order to improve compliance, the total daily dosage may thereafter be given as 80mg twice a day.
Hyperthyroidism
The dose is adjusted according to clinical response.
Portal Hypertension
Dosage should be titrated to achieve approximately 25% reduction in heart rate at rest. Dosing should begin with 40mg twice daily, increasing to 80mg twice daily depending on heart rate response. If necessary, the dose may be increased incrementally to a maximum of 160mg twice daily.
Phaeochromocytoma
(Used only with an alpha-receptor blocking drug).
Pre-operative: 60 mg daily for 3 days is recommended. Non-operable malignant cases: 30 mg daily.
Hepatic impairment:
The bioavailability of Obsidan may be increased in patients with hepatic impairment and dose adjustments may be required. In patients with severe liver disease (e.g. cirrhosis) a low initial dose is recommended (not exceeding 20mg three times a day) with close monitoring of the response to treatment (such as the effect on heart rate).
Renal impairment:
Concentrations of Obsidan may increase in patients with significant renal impairment and haemodialysis. Caution should be exercised when starting treatment and selecting the initial dose.
As with other beta-adrenoceptor blocking agents, treatment should not be discontinued abruptly. The dosage should be withdrawn gradually over a period of 7 to 14 days. Either the equivalent dosage of another beta-adrenoceptor blocker may be substituted or the withdrawal of Obsidan should be gradual. Patients should be followed during withdrawal especially those with ischaemic heart disease. The risk/benefit of stopping beta blockade should be made for each patient.
Elderly:
Evidence concerning the relationship between blood level and age is conflicting. Obsidan should be used to treat older people with caution. It is suggested that treatment should start with the lowest dose. The optimum dose should be individually determined according to clinical response.
Paediatric population
Arrhythmias
Dosage should be determined according to the cardiac status of the patient and the circumstances necessitating treatment. The dose should be adjusted individually and the following is a guide: Children and adolescents: 0.25-0.5 mg / kg 3-4 times daily, adjusted according to clinical response.
Migraine
Oral: Under the age of 12: 20 mg two or three times daily. Over the age of 12: The adult dose.
Method of administration
For oral administration.
Any unused product or waste material should be disposed of in accordance with local requirements.
