HALF BETA PROGRANE

Half Beta-Prograne 80 mg Prolonged-Release Capsules

Each capsule contains Propranolol Hydrochloride 80 mg

Excipients - Contains Sucrose 3mg and Sulphur Dioxide (E220)

For a full list of excipients, see section 6.1.

Prolonged release capsules, hard.

Capsules with opaque white cap and colourless, transparent body containing white microgranules.

Control of Hypertension

Management of angina pectoris

Management of essential tremors

Control of anxiety

Adjunctive management of thyrotoxicosis

Prophylaxis of migraine

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

Long-term prophylaxis after recovery from acute myocardial infarction.

For oral use. The capsule must not be chewed, but swallowed whole to ensure a prolonged release action.

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.

Adults

Hypertension:

The usual starting dose is one 160mg Beta-Prograne capsule daily, taken either morning or evening. An adequate response is seen in most patients at this dosage. If necessary, it can be increased in 80mg Half Beta-Prograne increments until adequate response is achieved.

A further reduction in blood pressure can be attained if a diuretic or other antihypertensive agent is given in addition to Half Beta-Prograne.

One Half-Beta-Prograne capsule 80mg daily is unlikely on its own to be sufficient to treat hypertension but it may be used as a starting dose in appropriate patients (e.g. the elderly) or to provide a convenient method of gradual dose alteration.

Angina, anxiety, essential tremor, thyrotoxicosis, propylaxis of migraine:

Adequate control is gained in most patients on one half Beta-Prograne 80mg capsule per day (either morning or evening). If necessary,the dose may be increased to one 160mg Beta-Prograne capsule per day and an additional Half Beta-Prograne increment may be given.

Patients who are already established on equivalent daily doses of Beta-Prograne capsules should be transferred to the equivalent doses of 80mg Half Beta-Prograne capsule or 160mg Beta-Prograne capsule taken either morning or evening.

Portal Hypertension/Oesophageal varices :

Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosing should begin with one Half Beta-Prograne 80mg Prolonged-Release Capsule daily, increasing to one Beta-Prograne 160mg Prolonged-Release Capsule daily depending on heart rate response. Further Half Beta-Prograne 80mg Prolonged-Release Capsule increments may be added up to a maximum dose of 320mg once daily.

Post Myocardial Infarction:

Treatment should start between days 5 and 21 after myocardial infarction with an initial dose of one Half Beta-Prograne 40mg tablet four times a day for 2 or 3 days. In order to achieve maximum compliance the total daily dosage of 160mg Beta-Prograne may be given thereafter as a single 160mg Beta-Prograne or two 80mg Half- Beta-Prograne tablet.

Renal or hepatic impairment

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

Elderly Patients

Evidence concerning the relation between blood level and age is conflicting. With regard to the elderly, the optimum dose should be individually determined according to clinical response.

Children

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules are not intended for use in children.

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules must not be taken if there is a history of bronchial asthma or bronchospasm.

Bronchospasm can usually be reversed by beta-2 agonist bronchodilators such as salbutamol. Large doses of the beta- 2 agonist bronchodilator may be required to overcome the beta-blockade produced by propranolol and the

dose should be titrated according to the clinical response; both intravenous and inhalation 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 2mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules, as with other beta-adrenoceptor blocking drugs, must not be used in patients with any of the following conditions:

- known hypersensitivity to the active substance or any of the excipients listed in section 6.1

- bradycardia

- cardiogenic shock

- hypotension

- metabolic acidosis

- after prolonged fasting

- severe peripheral arterial circulatory disturbances

- second or third degree heart block

- sick sinus syndrome

- untreated phaeochromocytoma

- uncontrolled heart failure or digitalis/diuretic refractory

- Prinzmetal’s angina

Beta-prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules must not be used in patients prone to hypoglycaemia, i.e. patients after prolonged fasting or patients with restricted counter-regulatory reserves. Patients with restricted counter regulatory reserves may have reduced autonomic and hormonal responses to hypoglycaemia which includes glycogenolysis, gluconeogenesis and/or

impaired modulation of insulin secretion. Patients at risk for an inadequate response to hypoglycaemia includes individuals with malnutrition, prolonged fasting, starvation, chronic liver disease, diabetes and concomitant use of

drugs which block the full response to catecholamines.

Beta-Prograne 160mg Prolonged-Release Capsules or Half Beta-Prograne 80mg Prolonged-release Capsules as with other beta-adrenoceptor blocking drugs:

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.

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.

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules must be used with caution in patients with decompensated cirrhosis (see Section 4.2).

When this agent is administered to patients in renal failure, the interval between doses may need to be increased or the dosage reduced to avoid accumulation of drug.

In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy (see Section 4.2).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Patients with rare hypersensitivity for sulphur dioxide should not take this medicine; which may cause hypersensitivity reactions and bronchospasm.

Interference with laboratory tests:

Beta-Prograne 160mg Prolonged-release Capsules or Half Beta-Prograne 80mg Prolonged-Release Capsules have been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.

If Beta-Prograne 160mg Prolonged-Release Capsule and Half Beta-Prograne 80mg Prolonged-Release Capsule is administered in conjunction with other antihypertensives an adjustment of dosage may be required.

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules modify the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin (see Section 4.3 and 4.4).

Adjustment of dosage of hypoglycaemic agents may be necessary if Beta-Prograne 160mg Prolonged-Release Capsule is given to patients with uncontrolled or ‘brittle’ diabetes mellitus.

Beta-Prograne 160mg Prolonged-Release Capsules or Half Beta-Prograne 80mg Prolonged-Release Capsules should be used with great caution in patients who are receiving concomitant myocardial depressants such as chloroform, ether or related anaesthetics, antiarrhythmic agents such as quinidine, lidocaine, procainamide (which accentuate depressant effects).

Simultaneous administration of rizatriptan and propranolol can cause an increased rizatriptan AUC and C max by approximately 70-80%. The increased rizatriptan exposure is presumed to be caused by inhibition of first-passage metabolism of rizatriptan through inhibition of monoamine oxidase-A. If both drugs are to be used, a rizatriptan dose of 5 mg has been recommended.

Caution must be exercised when prescribing a beta-adrenoceptor blocking drug with Class 1 antiarrhythmic agents such as disopyramide. Class I anti-arrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.

Digitalis glycosides, in association with beta-adrenoceptor blocking drugs, may increase atrio-ventricular conduction time.

Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects e.g. 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.

Concomitant therapy with dihydropyridine calcium channel blockers e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Concomitant use of sympathomimetic agents, e.g. adrenaline, may counteract the effect of beta-adrenoceptor blocking drugs. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta- adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result. Care should also be taken with preparations such as isoprenaline and noradrenaline.

Adrenergic neurone blocking agents (such as guanethidine and reserpine), diuretics and other antihypertensive agents, including the vasodilator group will have an additive effect on the antihypertensive action of the drug.

Administration of Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules 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.

Concomitant use of cimetidine will increase plasma levels of propranolol, and concomitant use of alcohol may increase , the plasma levels of propranolol.

Beta-adrenoceptor blocking drugs may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenceptor blocking drug therapy, the introduction of beta-adrenoceptor blocking drugs should be delayed for several days after clonidine administration has stopped.

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.

Concomitant use of prostaglandin synthetase inhibiting drugs, e.g. ibuprofen or indomethacin, may decrease the hypotensive effects of propranolol.

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.

Caution must be exercised when using anaesthetic agents with Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules. 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.

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 therapy with dihydropyridine calcium channel blockers).

Pregnancy:

As with all drugs, Beta- Prograne 160mg Prolonged- Release Capsules and Half Beta- Prograne 80mg Prolonged- Release Capsules should not be given during pregnancy unless their use is essential. There is no evidence of teratogenicity.

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.

There are no studies on the effect of propranolol on the ability to drive. Use is unlikely to result in any impairment of the ability of patients to drive or operate machinery. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

Beta-Prograne 160mg Prolonged-Release Capsules and Half Beta-Prograne 80mg Prolonged-Release Capsules are usually well tolerated. In clinical studies the adverse reactions reported are usually attributable to the pharmacological actions of propranolol.

The following possible undesired events, listed by frequency and body system, have been reported:

Common(1 – 9.9%)

General: Fatigue and/or lassitude (often transient)

Cardiovascular: Bradycardia, cold extremities, Raynaud’s phenomenon

CNS: Sleep disturbances, nightmares

Uncommon (0.1-0.9%)

GI: Gastrointestinal disturbance, such as nausea, vomiting, diarrhoea.

Rare (0.01-0.09%)

General: Dizziness.

Blood: Thrombocytopenia.

Cardiovascular: Heart failure deterioration, precipitation of heart block, Postural hypotension, which may be associated with syncope, exacerbation of intermittent claudication.

CNS: Hallucinations, psychoses, mood changes, confusion.

Skin: Purpura, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes.

Neurological: Paraesthesia.

Eyes: Dry eyes, visual disturbances.

Respiratory: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome.

Very rare (<0.01%)

Endocrine system: Hypoglycaemia in 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).

Investigations: An increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear.

Nervous system: Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported.

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.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

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.

Propranolol is a competitive antagonist at both 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-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 contra-indicated in uncontrolled heart failure.

Propranolol is a racemic mixture and the active form is the S (-) isomer. With the exception of inhibition of the conversion of thyroxine to triiodothyronine it is unlikely that any additional ancillary 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 populations, although the response may be less in black patients.

The sustained release preparation of propranolol maintains a higher degree of beta₁-blockade 24 hours after dosing compared with conventional propranolol.

Propranolol is completely absorbed after oral administration and peak plasma concentrations occur 1-2 hours after dosing in fasting patients. Following oral dosing with the sustained release preparation of propranolol, the blood profile is flatter than after conventional Propranolol tablets but the half-life is increased to between 10 and 20 hours. 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%).

There is no evidence of teratogenicity with propranolol.

Neutral microgranules (corn starch, sucrose).

Povidone.

Ethylcellulose.

Talc.

Capsule components:

Gelatin.

Titanium Dioxide (E171)

Sulphur Dioxide (E220)

Not applicable.

5years.

Do not store above 25^oC. Store in the original package.

Blister packs:

PVC: Colourless 250 micron thickness

Aluminium: 25 microns thickness.

28 capsules per pack, 14 capsules per blister strip.

Tillomed Laboratories Ltd

3 Howard Rd

Eaton Socon. St. Neots

Cambridgeshire PE19 8ET

United Kingdom

PA0644/001/002

Date of first authorisation: 25 June 1999

Date of last renewal: 25 June 2009

No special requirements.