SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Propranolol 10mg Tablets BP

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 10mg of propranolol hydrochloride.

For excipients see 6.1

3    PHARMACEUTICAL FORM

Film coated tablets

The tablets are pink, film-coated biconvex tablets embossed ‘10’ on one face.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

•    The control of hypertension.

•    The management of angina pectoris.

•    The long term prophylaxis after recovery from acute myocardial infarction.

•    The control of most forms of cardiac dysrhythmias.

•    The prophylaxis of migraine.

•    The management of essential tremor.

•    The relief of situational anxiety and generalised anxiety symptoms, particularly those of somatic type.

•    Prophylaxis of upper gastro-intestinal bleeding in patients with portal hypertension and oesophageal varices.

•    The adjunctive management of thyrotoxicosis and thyrotoxic crisis.

•    Management of hypertrophic obstructive cardiomyopathy.

•    Management of phaeochromocytoma perioperatively (with alpha blocker).

4.2    Posology and method of administration

Tablets are to be taken orally with a drink of water.

The lowest possible dose should be used initially in all patient groups, but this is particularly important in elderly patients. Subsequent increases in dose should be gradual.

Posology:

Adults:

Hypertension:

A starting dose of 80mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160-320mg per day. Lower doses may be effective when a diuretic or other antihypertensive drugs are given concurrently.

Angina, Migraine and Essential Tremor:

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

Situational and Generalised Anxiety:

In acute situational anxiety, a dose of 40mg daily may provide short term relief. In generalised anxiety requiring longer term therapy, an adequate response may be expected with 40mg twice daily which, in individual cases, may be increased to 40mg three times daily. Treatment should be continued according to response and patients should be reviewed after six to twelve months’ treatment.

Dysrhythmias, Anxiety Tachycardia, Hypertrophic Obstructive Cardiomyopathy and Thyrotoxicosis:

10-40mg three or four times a day.

Post Myocardial Infarction:

For long-term prevention of sudden cardiac death in patients who have survived the acute phase of myocardial infarct, treatment should start between days 5 and 21 after myocardial infarction, with an initial dose of 40mg four times a day for 2 to 3 days. In order to improve compliance the total daily dosage may thereafter be given as 80mg twice a day.

Portal Hypertension:

Dosage should be titrated to achieve approximately 25% reduction in resting heart rate, initially, 40mg 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:

Propranolol should be used only with an alpha-receptor blocking drug.

Pre-operative:

60mg daily for three days.

Non-Operable Malignant Cases:

30mg daily.

Children:

Arrhythmias, Phaeochromocytoma, Thyrotoxicosis:

Dosage should be determined individually. The following dosages are intended only as a guide.

0.25 - 0.50mg/kg three or four times daily as required. Adjusted according to response. Max 1mg/kg 4 times daily, total daily dose not to exceed 160 mg daily.

Migraine

Under the age of 12: 20mg two or three times daily. Over the age of 12: Similar to adult dose.

Fallot’s Tetralogy:

Propranolol is used mainly to relieve right-ventricular outflow tract shutdown. It is also useful for treatment of associated dysrhythmias and angina. Dosage should be individually determined and the following is only a guide:

Up to 1mg/kg repeated three or four times daily as required.

Elderly Patients:

The optimum, dose should be individually determined according to clinical response.

4.3 Contraindications

In patients with cardiogenic shock.

Uncontrolled heart failure.

Sick sinus syndrome (including sino-atrial block).

In patients with second or third degree heart block.

Prinzmetal’s angina (in case of non-selective beta-blockers).

If there is a history of bronchospasm and bronchial asthma or wheezing. Untreated phaeochromocytoma.

In metabolic acidosis (e.g. in some diabetics).

Bradycardia (<45 - 50 bpm).

Hypotension.

Hypersensitivity to the substance.

Severe peripheral arterial circulatory disturbances.

After prolonged fasting.

In patients prone to hypoglycaemia i.e., patients after prolonged fasting or patients with restricted counter-regulatory reserves.

4.4 Special warnings and precautions for use

In patients with ischaemic heart disease, sudden withdrawal of betaadrenoceptor blocking drugs may result in anginal attacks of increased frequency or severity. Therefore, withdrawal of Propranolol in patients with ischaemic heart disease should be gradual, i.e. over 1-2 weeks. If necessary at the same time initiating replacement therapy, to prevent exacerbation of angina pectoris.

In addition, hypertension and arrhythmias may develop. When it has been decided to interrupt a beta-blockade 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; however, the risk of hypertension may be increased as well. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. The patient may be protected against vagal reactions by intravenous administration of atropine.

Propranolol 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.

A reduction in heart rate is a pharmacological effect of Propranolol. In rare cases where symptoms may be attributable to the slow heart rate, the dose may be reduced. If the pulse rate decreases to less that 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, the dosage should be reduced.

Propranolol is contraindicated in patients with severe peripheral arterial circulatory disorders. In patients with less severe peripheral arterial circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), betablockers should be used with great caution as aggravation of these disorders may occur.

In patients with chronic obstructive pulmonary disorders, airway obstructions may be aggravated. Therefore, non-selective beta-blockers should not be used for these patients, and beta-1 selective blockers only with the utmost care.

Due to its negative effect on conduction time, beta -blockers should only be given with caution to patients with first degree heart block.

Patients with liver or kidney insufficiency may need a lower dosage, depending on the pharmacokinetic profile of the compound.

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.

The elderly should be treated with caution, starting with a lower dosage but tolerance is usually good in the elderly.

Propranolol should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly. Propranolol should be used with caution in patients with decompensated cirrhosis. Beta-blockers may increase the number and the duration of anginal attacks in patients with Prinzmetal’s angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Non-selective beta-blockers should not be used for these patients, and beta-1 selective blockers only with the utmost care.

Patients with anamnestically known psoriasis should take beta-blockers only after careful consideration.

Beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

Particular care is required with patients whose cardiac reserve is poor. Betaadrenoceptor

blocking drugs should be avoided in overt heart failure, although they may be used when signs of failure have been controlled.

Cardiac failure due to thyrotoxicosis may respond to Propranolol alone but if other adverse factors are also present, it is important to control signs of failure with digitalis and diuretics. Propranolol may mask the signs of thyrotoxicosis.

Propranolol may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Propranolol 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 propranolol has rarely presented with seizures and/or coma in isolated patients.

Caution must be exercised in the concurrent use of propranolol and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin (see section 4.3).

Hepatic function will deteriorate in patients with portal hypertension and hepatic encephalopathy may develop. It has been suggested that treatment with Propranolol may increase the risk of developing hepatic encephalopathy.

Care is required when transferring patients from Clonidine to a betaadrenoceptor blocking drug. If the two drugs are given concurrently, Clonidine should not be discontinued until several days after the withdrawal of the betaadrenoceptor blocking drug. Care is required with prescribing a betaadrenoceptor blocking drug with class I antidysrhythmic agent such as

Disopyramide. Beta-adrenoceptor blocking drugs should be used with caution in combination with Verapamil where ventricular function is impaired. The combination should not be given to patients with conduction abnormalities, nor should either drug be administered intravenously within 48 hours of discontinuing the other. Care is required during parenteral administration of preparations containing adrenaline to patients receiving beta-adrenoceptor

blocking drugs, as in rare instances vasoconstriction, hypertension and bradycardia may occur.

Heart block and congestive heart failure have been reported due to propranolol.

Care is required when administering anaesthetic agents to patients receiving Propranolol. The anaesthetist should always be informed of the use of betaadrenoceptor

blocking drug and the chosen anaesthetic should have as little negative inotropic activity as possible.

Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days.

When a patient is scheduled for surgery and a decision is made to discontinue beta-blocker therapy, this should be done at least 24 hours prior to the procedure. The risk/benefit of stopping beta-blockade should be made for each patient.

Propranolol has been reported to interfere with some laboratory tests, viz estimation of serum bilirubin by the diazo method and determination of catecholamines by fluorescence methods.

Due to the excipient lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

The product label will carry the following warning:

Do not take this medicine if you have a history of wheezing or asthma.

4.5 Interaction with other medicinal products and other forms of interaction Not recommended association:

Calcium antagonists:

Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects eg, verapamil, diltiazem, can lead to an exaggeration of these effects, particularly in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular 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:

Association with beta-blockers may increase atrio-ventricular conduction time. Clonidine:

Beta-Blockers increase the risk of “rebound hypertension”. When clonidine is used in conjunction with non-selective beta-blockers, such as propranolol, treatment with clonidine should be continued for some time after treatment with the beta-blocker has been discontinued.

Precautions for use:

Class 1 anti-arrhythmic drugs (e.g. disopyramide, quinidine) and amiodarone:

May have potentiating effect on atrial-conduction time and induce negative inotropic effect.

Insulin and oral antidiabetic drugs:

May intensify the blood sugar lowering effect (especially non-selective beta-blockers).

Beta-adrenergic blockade may prevent the appearance of signs of hypoglycaemia (tachycardia).

Anaesthetic drugs:

Administration of propranolol during infusion of lignocaine may increase the plasma concentration of lignocaine by approximately 30%. Patients already receiving propranolol tend to have higher lignocaine levels than controls. The combination should be avoided.

Caution must be exercised when using anaesthetic agents with propranolol tablets. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-adrenoceptor blocking drugs with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.

Cimetidine, hydralazine:

Induce increased plasma levels of hepatically metabolised beta-blockers. Alcohol:

May decrease the plasma levels of Propranolol.

Take into account:

Calcium antagonists:

The risk of hypotension may be increased with dihydropyridine derivates such as nifedipine. In patients with latent cardiac insufficiency, treatment with betablocking agents may lead to cardiac failure.

Prostaglandin synthetase inhibiting drugs e.g. ibuprofen or indomethacin:

May decrease the hypotensive effects of beta-blockers.

Sympathomimetic agents:

May counteract the effects of beta blockers.

Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as other antihypertensive agents, may increase the blood pressure lowering effect.

Parenteral administration of preparations containing adrenaline to patients taking beta-adrenoceptor blocking drugs may, in rare cases, result in vasoconstriction, hypertension and bradycardia. Propranolol may prolong the hypoglycaemic response to insulin.

Beta-adrenoceptor blocking drugs may enhance the negative inotropic action of verapamil, class I antidysrhythmic agents such as disopyramide and certain anaesthetic agents.

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.

Pharmacokinetic studies have shown that the following agents may interact with propranolol due to effects on enzyme systems in the liver which metabolise propranolol and these agents: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed according to clinical judgement, (see also the interaction above concerning concomitant therapy with dihydropyridine calcium channel blockers).

Caution must be exercised if ergotamine, dihydroergotamine or related compounds are given in combination with Propranolol since vasospastic reactions have been reported in a few patients.

4.6 Pregnancy and lactation

The safety of Propranolol in pregnancy has not been established and its use should be avoided unless the potential benefits are likely to outweigh the possible risk to the foetus.

Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse affects (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.

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.

4.7 Effects on ability to drive and use machines

Propranolol is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

Propranolol tablets are usually well tolerated. In clinical studies, the undesired events reported are usually attributable to the pharmacological actions of propranolol.

The following undesired events, listed by body system, have been reported.

Cardiovascular: bradycardia, heart failure deterioration, postural hypotension which may be associated with syncope, cold cyanotic extremities. In susceptible patients: precipitation of heart block, exacerbation of intermittent claudication, Raynaud's phenomenon.

CNS: confusion, dizziness, mood changes, nightmares, psychoses and hallucinations, sleep disturbances, headache.

Endocrine: 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 (see section 4.3, 4.4 and 4.5).

Frequency of hypoglycaemia is not known in children.

Gastrointestinal: gastrointestinal disturbance.

Haematological: purpura, thrombocytopenia, there have been rare reports of blood dyscrasias during treatment propranolol.

Integumentary: alopecia, dry eyes, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes.

Neurological: paraesthesia. Seizures linked to hypoglycaemia.

Respiratory: bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome (see Section 4.3).

Special senses: visual disturbances.

Others: fatigue and/or lassitude (often transient), an increase in ANA (antinuclear antibodies) has been observed, however the clinical relevance of this is not clear; isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported in patients administered propranolol. 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-adrenoceptor blocking drug 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.

Minor side effects include cold extremities, nausea, vomiting, diarrhoea, fatigue or insomnia. These are usually transient and are less common if the drug is introduced gradually.

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

Symptoms of overdose are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency, hypoglycaemia, delirium and unconsciousness.

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1 to 2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1 to 10 mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10

microgram/kg/minute by intravenous infusion may be given. Dobutamine, because of its positive inotropic effect, could also be used to treat hypotension and acute cardiac insufficiency. 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.

Bronchospasm may be treated by nebulized salbutamol or intravenous aminophylline or salbutamol. Severe cases may require the use of oxygen or artificial ventilation.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Propranolol 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 3mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta-adrenoceptor 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.

Propranolol as with other beta-adrenoceptor blocking drugs, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.

Propranolol is a racemic mixture and the active form is the S (-) isomer of propranolol. With the exception of inhibition of the conversion of thyroxine to triiodothyronine, it is unlikely that any additional ancilliary properties possessed by R (+) propranolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.

Propranolol is effective and well tolerated in most ethnic groups, although the response may be less in black patients.

5.2 Pharmacokinetic properties

Following intravenous administration the plasma half-life of propranolol is about 2 hours and the ratio of metabolites to parent drug in the blood is lower than after oral administration. In particular, 4-hydroxypropranolol is not present after intravenous administration. Propranolol is completely absorbed after oral administration and peak plasma concentrations occur 1 to 2 hours after dosing in fasted patients. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Propranolol is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Propranolol is highly protein bound (80 to 95%).

5.3 Preclinical safety data

There is no pre-clinical data of relevance to a prescriber, which is additional to that already included in other sections of the Summary of Product Characteristics.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose

Talc

Stearic acid Magnesium stearate,

Hypromellose Polyethylene glycol Titanium dioxide (E171)

Carmine (E120)

6.2 Incompatibilities

There are no known major incompatibilities with Propranolol tablets.

6.3 Shelf life

Securitainers: 5 years Blisters: 3 years

6.4    Special precautions for storage

Do not store above 25°C Store in the original container

6.5    Nature and contents of container

The product is available in:

1)    Securitainers (High Density Polypropylene Container and Low Density Polyethylene Cap). Pack sizes: 20, 50, 500 and 1000 tablets.

2)    Blisters strips (20pm aluminium foil / clear 250pm PVC / 40gsm PVdC). Pack sizes: 28 Tablets.

6.6    Special precautions for disposal

No special instructions necessary

7    MARKETING AUTHORISATION HOLDER

RelonChem Limited Cheshire House, Gorsey Lane,

Widnes, Cheshire,

WA8 0RP UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20395/0033

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/03/2004 / 22/09/2010

10 DATE OF REVISION OF THE TEXT

24/09/2015