SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bedranol* (Propranolol Hydrochloride) Tablets 80mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains propranolol hydrochloride BP 80mg.

3    PHARMACEUTICAL FORM

Tablet.

Pink, round, film-coated tablets with P and 3 on either side of the score line and plain on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Bedranol* is a competitive blocker of adrenergic P-receptor sites. It is indicated in:

a)	The control of hypertension.
b)	The management of angina pectoris.
c)	The prevention of re-infarction after recovery from acute myocardial infarction.
d)	The control of most forms of cardiac arrhythmias including sinus tachycardia due to thyrotoxicosis, paroxysmal supraventricular tachycardia, atrial fibrillation and atrial flutter, ventricular extrasystoles, ventricular tachycardia and ventricular fibrillation (prophylaxis only), arrhythmias due to digitalis intoxication (if phenytoin cannot be used and no AV-block II or III is present).
e)	The adjunctive therapy in thyrotoxicosis.
f)	The prophylaxis of migraine.
g)	The management of essential tremor.
h)	The management of phaeochromocytoma (with an alpha-blocker).

4.2 Posology and method of administration

Dosage requires individual adjustment. The lowest appropriate dose should be given initially to be able to identify cardiac decompensation or bronchial phenomena at an early stage. Subsequent increases in dose should take place slowly on the basis of clinical response. A heart rate of 55/minute or less is an indication that dosage should be increased no further.

Adults:

Hypertension: Initially, 80mg, twice daily, increased where necessary at weekly intervals. The usual maintenance dosage is 160mg to 320mg daily. Lower doses may be effective when a diuretic or other antihypertensive drug is given concurrently.

Angina pectoris: Initially, 40mg, 2 or 3 times daily, increased by the same amount at weekly intervals until control is achieved, or the maximum daily dose of 480mg is reached.

Post myocardial infarction: Treatment should start between day 5 and 21 after myocardial infarction, with an initial dose of 40mg, 4 times a day for 2 to 3 days. In order to improve compliance the total daily dosage may thereafter be given as 80mg twice daily.

Dysrhythmias, thyrotoxicosis: 10mg to 40mg, 3 or 4 times daily.

Migraine, essential tremor: 40mg, 2 or 3 times daily, increased at weekly intervals, if needed, to a daily total of 80mg to 160mg.

Phaeochromocytoma:

Pre-operative: 60mg daily for 3 pre-operative days, always in association with an alpha-receptor blocking drug.

Non-operable malignant cases: 30mg daily.

Elderly:

The evidence concerning the relationship between blood level and age is conflicting. It is advisable to start with low initial doses, although tolerance is usually good in the elderly.

Patients with renal and hepatic dysfunction:

The half life of propranolol may be increased in patients with severe renal or hepatic impairment. Due caution should therefore be exercised when initiating treatment and selecting the dose to be employed.

Children:

Dysrhythmias, phaeochromocytoma, thyrotoxicosis: Dose should be determined according to the cardiac status of the patient and circumstances necessitating treatment. These doses are therefore only a guide: the minimum effective dosage based on 0.25mg/kg to 0.5mg/kg body weight, 3 or 4 times daily.

Migraine: Children under the age of 12 may be given 20mg, 2 or 3 times daily. Older children may be given adult dosage.

Method of administration: Oral.

4.3 Contraindications

Propranolol must not be used if any of the following conditions are present:

-    Cardiogenic shock

-    Uncontrolled heart failure

-    Sick sinus syndrome (including sino-atrial block)

-    Second and third degree heart block

-    Prinzmetal’s angina

-    History of bronchospasm and bronchial asthma

-    History of chronic obstructive pulmonary disease

-    Untreated phaeochromocytoma

-    Metabolic acidosis

-    After prolonged fasting or prone to hypoglycaemia

-    Bradycardia

-    Hypotension

-    Hypersensitivity to propranolol or any of the other ingredients

-    Severe peripheral arterial disease.

4.4 Special warnings and precautions for use

One of the pharmacological actions of propranolol is to reduce the heart rate; in the instance when symptoms may be attributable to slow heart rate, the dose may be reduced.

Patients with a history of wheezing or asthma should not take propranolol unless it is considered essential. The label will carry the following warning: “Do not take this medicine if you have a history of wheezing or asthma”.

The patient information leaflet will state “Do not take this medicine if you have a history of wheezing or asthma. Consult your doctor or pharmacist first”. Intolerance to propranolol, shown as bradycardia and hypotension may occur, in which case propranolol should be withdrawn. If necessary, treatment for overdose should be started.

Beta adrenoceptor blocking drugs 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. Particular caution is necessarily, when beta adrenoceptor blocking drugs are used in patients with a history of anaphylaxis.

In patients with ischaemic heart disease treatment must not be discontinued abruptly. Either the equivalent dose of another beta-blocker may be substituted, or the withdrawal of Bedranol* (Propranolol hydrochloride) should be gradual. This can be carried out by substituting the equivalent dose in propranolol 40mg tablets and then reducing the dose.

Bedranol* (Propranolol hydrochloride) should be used with caution in patients whose cardiac reserve is poor. Beta-adrenoceptor blocking drugs should be avoided in overt heart failure; however, they may be used in patients whose signs of failure have been controlled.

Bedranol* (Propranolol hydrochloride) may aggravate peripheral arterial circulatory disturbances beta adrenoreceptor blocking drugs may also aggravate less severe forms. Therefore, propranolol should be used with great caution in conditions such as Raynaud's disease/syndrome or intermittent claudication.

As propranolol has a negative effect on conduction time, care must be taken when giving it to patients with first degree heart block.

Care must be taken in patients with renal or hepatic dysfunction when beginning treatment and choosing the initial dose.

Bedranol* (Propranolol hydrochloride) should be used with care in patients with decompensated cirrhosis.

In patients with portal hypertension, liver function may deteriorate. There have been reports that treatment with propranolol may increase the risk of developing hepatic encephalopathy.

Propranolol, as with other beta-blocking drugs may block the symptoms of hypoglycaemia (especially tachycardia). It may even cause hypoglycaemia 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. It has rarely caused seizures and/or coma in isolated patients. Caution should be exercised in the concurrent use of propranolol therapy in diabetic patients as it may prolong the hypoglycaemic response to insulin.

Heart failure due to thyrotoxicosis often responds to propranolol alone, but if other adverse factors co-exist myocardial contractility must be maintained and signs of failure controlled with digitalis and diuretics. Propranolol may mask the important signs of thyrotoxicosis and hyperthyroidism.

Since the half-life may be increased in patients with significant hepatic or renal impairment, care should be taken when starting treatment and selecting the initial dose.

Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported in patients administered propranolol.

Psoriasis may be aggravated by the use of beta adrenoreceptor blocking drugs.

Beta adrenoreceptor blocking drugs should not be used in untreated phaeochromocytoma (See section 4.3), however, in patients with phaeochromocytoma an alpha-blocker may be given concomitantly.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Withdrawal

Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. In the rare event of intolerance, manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted. The sudden withdrawal of beta-receptor antagonists may result in severe exacerbation of angina pectoris, acute myocardial infarction, sudden death, malignant tachycardia, sweating, palpitation and tremor. Withdrawal should be accomplished over 10 to 14 days however caution must be exercised as this does not always prevent rebound effects.

When withdrawing a beta-blocker in preparation for surgery, therapy should be discontinued for at least 24 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, although there may be an increased risk of hypertension. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs and the chosen anaesthetic should have as little negative inotropic activity as possible. The anaesthetist should always be informed about the use of a beta-blocking drug. The patient may be protected against vagal reactions by the intravenous administration of atropine.

4.5 Interaction with other medicinal products and other forms of interaction

Adrenaline (epinephrine):

Care should be taken in the parenteral administration of preparations containing adrenaline (epinephrine) to patients taking beta-adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result.

Care should be taken when using anaesthetic agents with propranolol. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible.

It may be necessary to withdraw Bedranol* (Propranolol hydrochloride) before surgery (24 hours should be allowed to elapse between the last dose and anaesthesia). If Bedranol* (Propranolol hydrochloride) is continued throughout surgery the anaesthetist should be told and care should be taken in selecting and using suitable anaesthetic agents (note bupivacaine toxicity with propranolol). An anaesthetic agent with as little myocardial depression as possible should be used. Beta-blockers used with anaesthesic agents may result in attenuation of reflex tachycardia and the risk of hypotension may increase.

Anti-arrhythmics:

Caution must be exercised in co-prescribing beta-adrenoceptor blockers with Class I anti-arrhythmic agents such as disopyramide, quinidine, flecainide and amiodarone may have potentiating effects on arterial conduction time and induce negative inotropic effect. Administration of propranolol during infusion of lidocaine may increase the plasma concentration of lidocaine by approximately 30%. Patients already receiving propranolol tend to have higher lidocaine levels than controls. The combination should be avoided.

Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects eg verapamil, diltiazem can lead to prolongation of SA and AV conduction particularly in patients with impaired ventricular function or conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-adrenoceptor blocking drug nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other. Digitalis glycosides used in association with beta-adrenoceptor blockers may increase AV conduction time.

Anticoagulants:

Propranolol may cause a reduction in clearance and an increase in plasma concentrations of warfarin.

Antidiabetic drugs:

Propranolol modifies the tachycardia of hypoglycaemia and care should be taken when treating diabetic patients with Bedranol* (Propranolol hydrochloride) whether or not they are also taking hypoglycaemic agents. Propranolol may prolong the hypoglycaemic response to insulin.

Beta-adrenoceptor blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the drugs are coadministered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine with beta-adrenoceptor therapy the introduction of the beta-adrenoceptor blocking drug should be delayed for several days after clonidine administration has stopped. Concomitant use of moxonidine and beta blockers may result in an enhanced hypotensive effect. The steps for moxonidine withdrawal/introduction should be the same as for clonidine. Hypotensive effect may be enhanced when propranolol is taken with diuretics, methyldopa or levodopa.

Prazosin or other alpha-adrenoreceptor blockers may potentiate postural hypotension, tachycardia and palpitations.

Digitoxin or digoxin taken at the same time as beta-blockers can increase atrioventricular conduction time.

Antimigraine drugs:

Caution is necessary if ergotamine, dihydroergotamine or related compounds are given in combination with propranolol since vasopastic reactions have been reported in a few patients. Propranolol inhibits the metabolism of rizatriptan which can significantly increases plasma concentration levels. A dose reduction to 5mg is recommended. Administration should be separated by 2 hours.

Barbiturates: The metabolism of propranolol may be increased by potent liver enzyme inducer barbiturates.

Chlorpromazine:

Concomitant administration of propranolol and chlorpromazine may result in an increase in plasma levels of both drugs. This may lead to an enhanced antipsychotic effect for chlorpromazine and an increased antihypertensive effect for propranolol.

Cimetidine:

Concomitant use of cimetidine will increase, where as alcohol will decrease the plasma levels of propranolol.

Hydralazine:

Concomitant use of hydralazine will increase, where as alcohol will decrease the plasma levels of propranolol.

Imipramine:

Propranolol may cause plasma concentrations of imipramine to increase.

Monamine-oxidase Inhibitors:

The hypotensive effects of beta-blockers may be enhanced by MAOIs. Non-steroidal anti-inflammatory drugs:

NSAIDs notably indometacin, may cause an increase in blood pressure. This may be particularly significant in patients with poorly controlled hypertension.

Rifampicin:

The metabolism of propranolol may be increased by potent liver enzyme inducer rifampicin.

Selective Serotonin Re-uptake Inhibitors:

Fluvoxamine inhibits oxidative metabolism and increases plasma concentrations of propranolol. This may result in severe bradycardia.

Theophylline:

Propranolol reduces the clearance and consequentially increases the plasma concentration of theophylline.

Tobacco:

Smoking tobacco may oppose the effects of beta blockers in the treatment of angina or hypotension. Patients should be encouraged to stop smoking, apart from its other toxic effects, it aggravates myocardial ischaemia, increases heart rate and can impair blood pressure control. If patient continues to smoke, dosage of the beta blocker may need to be increased or a cardio-selective beta blocker may be more appropriate.

Interference with laboratory tests: Propranolol 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.

4.6 Fertility, Pregnancy and lactation

Pregnancy

As with all other drugs, propranolol should not be given in pregnancy or lactation unless its use is essential. There is no evidence of teratogenicity with propranolol. However beta-adrenoceptor blocking drugs reduce placental perfusion, which may result in intra-uterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foetus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.

Lactation

Most beta-adrenoceptor blocking drugs, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.

4.7 Effects on ability to drive and use machines

The use of propranolol is unlikely to result in any significant impairment of the ability of patients to drive or operate machinery. However, patients should be warned that visual disturbances, hallucinations, mental confusion, dizziness, drowsiness or fatigue may occur and they should not drive or operate machinery if they feel affected.

4.8. Undesirable effects

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).

The following undesired events, listed by body system, have been reported: Blood and lymphatic system disorders Rare: thrombocytopenia,

Frequency not known: agranulocytosis,

Endocrine disorders

Frequency not known: masking signs of thyrotoxicosis.

Metabolic and nutritional disorders

Frequency not known: 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 and seizures linked to hypoglycaemia has been reported.

Frequency not known: changes in lipid metabolism (changes in blood concentrations of triglycerides and cholesterol)

Common: Sleep disturbances, nightmares.

Frequency not known: depression, confusion Nervous system disorders

Rare: Hallucinations, psychoses, mood changes, confusion, memory loss, dizziness, paraesthesia.

Very rare: Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported.

Frequency not known: headache, seizure linked to hypoglycaemia.

Eye disorders

Rare: visual disturbances, dry eyes Frequency not known: conjunctivitis Cardiac disorders

Common: bradycardia

Rare: Heart failure deterioration, precipitation of heart block, postural hypotension which may be associated with syncope,

Frequency not known: worsening of attacks of angina pectoris

Vascular disorders

Common: cold extremities, Raynaud's syndrome

Rare: exacerbation of Intermittent claudication,

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm may occur in patients with bronchial asthma or a

history of asthmatic complaints, sometimes with fatal outcome.

Frequency not known: dyspnoea.

Gastrointestinal disorders

Uncommon: diarrhoea, nausea, vomiting

Frequency not known: constipation, dry mouth

Rare: alopecia, purpura, psoriasiform skin reactions, exacerbation of psoriasis, rash

Musculoskeletal system and connective tissue disorders Frequency not known: arthralgia Renal and urinary disorders

Frequency not known: reduced renal blood flow and GFR Reproductive system and breast disorders Frequency not known: sexual dysfunction General disorders and administration site conditions Common: fatigue and/or lassitude (often transient) Investigations:

Very rare: An increase in ANA (antinuclear antibodies) has been observed with many beta blockers, however the clinical relevance of this is not clear.

Discontinuance of the drug should be considered if, according to clinical judgement, the well being of the patient is adversely affected by any of the above reactions. Cessation of therapy with a beta-blocker should be gradual (see section 4.4). In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted (see section 4.9).

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

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 preexisting airways disease. Hypoglycaemia and hypocalcaemia are rare and occasionally generalised spasm may also be present.

Management

In cases of overdose or extreme falls in the heart rate or blood pressure, treatment with propranolol must be stopped. In addition to primary poison elimination measures, vital parameters must be monitored and corrected accordingly in intensive care.

This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal (50g for adults, 1g/kg for children) if an adult presents within 1 hour of ingestion of more than a therapeutic dose or a child for any amount. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.

Bradycardia may respond to large doses of atropine (3 mg intravenously for an adult and 0.04 mg/kg for a child).

For severe hypotension, heart failure or cardiogenic shock in adults a 510mg 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 there is severe bradycardia and hypotension, which is not improved by glucagon, isoprenaline at an infusion rate of 5-10 micrograms/minute (0.02 micrograms/kg/min in children increasing to a maximum of 0.5 micrograms/kg/min) and increased as necessary depending on clinical response.

In sever hypotension additional inotropic support may be necessary with a beta agonist such as dobutamine 2.5-40 micrograms/kg/min (adults and children).

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).

5.1 Pharmacodynamic properties

Propranolol is a non-cardioselective, competitive blocker of adrenergic Preceptor sites.

5.2 Pharmacokinetic properties

Following oral administration of propranolol hydrochloride peak plasma levels occur approximately 1 to 2 hours after an oral dose. Individual plasma concentrations vary. The plasma half-life of propranolol is about 3 to 6 hours. Propranolol binds well to plasma proteins. It has high solubility, and crosses the blood-brain barrier, placenta and enters breast milk.

Propranolol is absorbed almost completely from the gastrointestinal tract, but binds to hepatic tissue where it is subject to first-pass metabolism.

Propranolol is metabolised in the liver, and excreted in the urine as metabolites and unchanged drug.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose, maize starch, soluble starch, sodium starch glycollate, microcrystalline cellulose, magnesium stearate, hypromellose 50, ethylcellulose 45, diethylphthalate and erythrosine (E127).

6.2 Incompatibilities

Not known.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Securitainers with polyethylene closures. Pack size: 500.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0066

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

7 July 1982/9 September 1992

10 DATE OF REVISION OF THE TEXT

10/08/2016