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Actavis UK Ltd

Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
Telephone: +44 (0)1271 311 200
Fax: +44 (0)1271 346 106
WWW: http://www.actavis.co.uk
Medical Information Direct Line: +44 (0)1271 311 257
Medical Information e-mail: medinfo@actavis.co.uk

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Summary of Product Characteristics last updated on the eMC: 16/02/2012

Propranolol Tablets BP 10mg



1. Name of the medicinal product

PROPRANOLOL TABLETS BP 10mg


2. Qualitative and quantitative composition

Each tablet contains 10mg Propranolol Hydrochloride PhEur.


3. Pharmaceutical form

Pink film-coated tablets.

Pink, circular, biconvex film-coated tablets impressed “C” on one face and the identifying letters “P” and “A” on either side of a central division line on the reverse.


4. Clinical particulars

4.1 Therapeutic indications

1) Management of angina pectoris.

2) Control of hypertension.

3) Long-term prophylaxis against re-infarction after recovery from acute myocardial infarction.

4) Management of hypertrophic obstructive cardiomyopathy.

5) Management of essential tremor.

6) Relief of situational anxiety and generalised anxiety symptoms, particularly those of somatic type.

7) Control of most forms of cardiac arrhythmia.

8) Adjunctive management of thyrotoxicosis and thyrotoxic crisis.

9) Management of phaeochromocytoma peri-operatively (with an alpha-blocker).

10) Prophylaxis of migraine.

11) Prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices.


4.2 Posology and method of administration

The tablets should preferably be administered before meals.

Adults and children over 12 years:

Angina, migraine and essential tremor: Initially 40mg two or three times daily, increasing by the same amount at weekly intervals according to response. An adequate response in migraine and essential tremor is usually seen in the range 80-160mg daily, and in angina 120-240mg daily.

Hypertension: Initially 80mg twice daily, which may be increased at weekly intervals according to response. The usual dose range is 160-320mg/daily. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.

Arrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: Most patients respond within the dosage range of 10-40mg three or four times daily.

Situational and generalised anxiety: A dose of 40mg daily may provide short term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately to 40mg twice daily which, in individual cases, may be increased to 40mg three times daily. Treatment should be continued according to response. Patients should be reviewed after six to twelve months' treatment.

Post myocardial infarction: Treatment should be initiated between days 5-21 after myocardial infarction, with an initial dose of 40mg four times daily for two or three days. In order to improve compliance, the total daily dosage may thereafter be given as 80mg twice a day.

Phaeochromocytoma (used only in conjunction with an alpha-receptor blocking drug): Pre-operatively; 60mg daily for three days is recommended. Non-operable malignant cases, 30mg daily.

Portal Hypertension: Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. 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.

Children and Adolescent:

Arrhythmias: Dosage should be determined according to the cardiac status of the patient and the circumstances necessitating treatment. The doses given are intended only as a guide: 0.25-0.5mg/kg bodyweight three or four times daily as required.

Elderly: Evidence concerning the relationship between blood level and age is conflicting. The optimum dose should be individually determined according to clinical response.

Hepatic impairment

The bioavailability of propranolol 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 propranolol may increase in patients with significant renal impairment and haemodialysis. Caution should be exercised when starting treatment and selecting the initial dose.

For oral use.


4.3 Contraindications

Hypersensitivity to propranolol or to any of the excipients; the presence of second or third degree heart block; cardiogenic shock; a history of bronchospasm or bronchial asthma, chronic obstructive airways disease; after prolonged fasting (ie hypoglycaemia); in metabolic acidosis (eg in diabetes); bradycardia(heart rate <45-50 beats/min); hypotension; severe peripheral arterial disturbances; sick sinus syndrome; Prinzmetal's angina; untreated phaeochromocytoma. Its use may lead to hypertensive crisis.

The product labelling and patient information leaflet will include a suitable warning regarding taking the medicine with a history of wheezing or asthma.


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.

Special care should be taken with 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.

Caution must be exercised if propranolol is given to patients with first degree heart block.

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.

As with other beta-adrenoceptor blocking agents, in patients with ischaemic heart disease, treatment should not be discontinued abruptly. Either the equivalent dosage of another beta-adrenoceptor blocker may be substituted or the withdrawal of propranolol should be gradual.

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.

Propranolol should be used with caution in patients with decompensated cirrhosis.

Liver function will deteriorate in patients with portal hypertension and hepatic encephalopathy may develop. There have been some reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy.

Although contraindicated in severe peripheral 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.

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.

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.

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.

Anaesthetics:

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.

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; caution should therefore be exercised in the concomitant use of propranolol and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Antihypertensives:

Beta-adrenoceptor blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the drugs are co-administered, 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.

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-steriodal 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 ocardial 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.

Laboratory tests:

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. 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 has been reported. Changes in lipid metabolism (changes in blood concentrations of triglycerides and cholesterol)

Psychiatric disorders

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: exacerbaction 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

Skin and subcutaneous tissue disorders

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).


4.9 Overdose

Clinical features:

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.

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 (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. 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 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, 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 severe 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. Pharmacological properties

5.1 Pharmacodynamic properties

ATC code: C07A A05

Propranolol hydrochloride is a beta-adrenoceptor blocking agent.

Mode of Action

Propranolol is a competitive antagonist at both beta, and beta2-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1-3mg/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.


5.2 Pharmacokinetic properties

Propranolol is almost completely absorbed from the gastrointestinal tract, but it is subject to considerable first-pass metabolism. Peak plasma concentrations occur about 2 hours after a dose. It is metabolised in the liver, the metabolites being excreted in the urine together with only small amounts of unchanged Propranolol; at least one of its metabolites is considered to be biologically active.

The biological half-life of Propranolol is longer than would be anticipated from its plasma half-life of about 3-6 hours.


5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.


6. Pharmaceutical particulars

6.1 List of excipients

The tablets contain: lactose, magnesium stearate, maize starch, stearic acid, hypromellose (E464).

The coating contains: carmoisine (E122), hypromellose (E464), polysorbate, titanium dioxide (E171), iron oxide red (E172).


6.2 Incompatibilities

None known.


6.3 Shelf life

Three years from the date of manufacture.


6.4 Special precautions for storage

Do not store above 25°C.


6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs and cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.


6.6 Special precautions for disposal and other handling

Not applicable.


Administrative data

7. Marketing authorisation holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS


8. Marketing authorisation number(s)

PL 0142/0139


9. Date of first authorisation/renewal of the authorisation

5.2.80

(Renewed: 5.2.85; 5.2.90; 25.6.95)


10. Date of revision of the text

01.02.2012