SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Avaprop 160 Retard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains propranolol hydrochloride BP 160 mg.

3 PHARMACEUTICAL FORM

Modified release capsule.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Avaprop 160 Retard is a competitive blocking agent of adrenergic ^-receptor sites. It is used in the treatment of hypertension and angina.

4.2 Posology and method of administration

Adults:

1) Hypertension

The initial dose is one capsule daily taken orally in the morning or evening. An adequate response is seen by most patients at this dosage. If necessary the dose can be increased to 2 capsules. A further reduction in blood pressure may be achieved by combining Avaprop 160 Retard with other anti-hypertensive agents.

2) Angina

Most patients will respond to one capsule daily taken orally in the morning or evening.

Children:

Avaprop 160 Retard is not intended for use in children.

Elderly:

The evidence concerning the relationship between blood level and age is conflicting. For patients already established on 160 mg propranolol daily, one capsule of Avaprop 160 Retard may be given. It is suggested that elderly patients being started off on propranolol treatment may need smaller initial doses and in these circumstances an alternative preparation should be used.

Method of Administration: Oral.

4.3 Contraindications

Avarop 160 Retard must not be used if there is a history of bronchial asthma or bronchospasm. The product label states the following warning: “Do not take Avarop 160 Retard if you have a history of asthma or wheezing”. A similar warning appears in the Patient Information Leaflet.

Bronchospasm can usually be reversed by beta₂ agonist bronchodilators such as salbutamol. Large doses of the beta₂agonist 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 inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2 mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.

Avarop 160 Retard, as with other beta-blockers, must not be used in patients with any of the following conditions: known hypersensitivity to the substance, 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 Prinzmetal's angina.

Avarop 160 Retard must not be used 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

Avaprop 160 Retard as with other beta-blockers:

•    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.

•    should not be used in patients with Prinzmetal's angina and beta-1 selective agents should be used with care. (see section 4.3).

•    although contra-indicated in severe peripheral arterial circulatory disturbances (see Section 4.3) may also aggravate less severe peripheral arterial circulatory disturbances.

•    due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.

•    may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Avaprop 160 Retard occasionally causes hypoglycaemia, even in nondiabetic patients, e.g., elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with Avaprop 160 Retard has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of Avaprop 160 Retard and hypoglycaemic therapy in diabetic patients. Avaprop 160 Retard may prolong the hypoglycaemic response to insulin. (see section 4.3).

•    may mask the signs of thyrotoxicosis.

•    should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.

•    should be used to treat the elderly with caution starting with a lower dose. (see section 4.2).

•    will reduce heart rate as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms that may be attributable to a slow heart rate, the dose may be reduced.

•    may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

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”.

Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days. An equivalent dosage of another beta-blocker may be substituted during the withdrawal period to facilitate a reduction in dosage below Avarop 160 Retard. Patients should be followed during withdrawal especially those with ischaemic heart disease.

When a patient is scheduled for surgery and a decision is made to discontinue beta-blocker therapy, this should be done at least 24 hours prior to the procedure.

Avaprop 160 Retard should be used with caution in patients whose cardiac reserve is poor. It should be avoided in overt heart failure but may be used where the signs of heart failure are controlled. In patients with ischaemic heart disease treatment should not be discontinued abruptly. Either the equivalent dose of another beta-blocker may be substituted or the withdrawal of Avaprop 160 Retard should be gradual. This can be done by substituting the equivalent dose in Propranolol Tablets 40 mg and then reducing the dose.

The risk/benefit of stopping beta blockade should be made for each patient. Avarop 160 Retard must be used with caution in patients with decompensated cirrhosis.

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

Care should be exercised when treating patients with renal impairment as it has been suggested that a reduced initial dosage is given.

Hepatic metabolism is a major route of elimination and therefore patients with liver disease may need to be given a reduced dosage. In these circumstances this preparation is not recommended.

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

Caution should be exercised when transferring patients from clonidine to beta-adrenoceptor blocking drugs.

Interference with laboratory tests: Avarop 160 Retard has been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using florescence.

4.5 Interaction with other medicinal products and other forms of interaction

If Avaprop 160 Retard and clonidine are given concurrently, clonidine should not be discontinued until several days after withdrawal of the beta-blocker.

Propranolol modifies the tachycardia of hypoglycaemia. Caution should be exercised in the concurrent use of Avaprop 160 Retard and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Concomitant use of sympathomimetic agents, eg, adrenaline, may counteract the effect of beta-blockers. Care should be taken 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.

Class I anti-arrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.

As with all beta-blocking drugs it may be necessary to withdraw Avaprop 160 Retard before surgery. Twenty-four hours should be allowed to elapse between the last dose and anaesthesia.

If Avaprop 160 Retard treatment is continued throughout surgery the anaesthetist should be informed and care should be taken when using anaesthetic agents such as ether, cyclopropane and trichloroethylene. Vagal dominance if it occurs may be corrected by 1-2mg I.V. atropine.

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.

Digitalis glycosides, in association with beta-blockers, may increase atrio-ventricular conduction time.

Combined use of beta-blockers 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 atrioventricular 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.

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

Concomitant use of sympathomimetic agents, eg, adrenaline, may counteract the effect of beta-blockers. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta-blockers as, in rare cases, vasoconstriction, hypertension and bradycardia may result.

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.

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

Beta-blockers may exacerbate the rebound hypertension, which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers 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, eg, ibuprofen or indometacin, 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 Avaprop 160 Retard 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-blockers 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 concomitant therapy with dihydropyridine calcium channel blockers).

4.6 Pregnancy and lactation

Pregnancy: As with all drugs, Avaprop 160 Retard should not be given during pregnancy unless their use is essential. There is no evidence of teratogenicity with Avarop 160 Retard . However beta-blockers 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-blockers, 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 Avarop 160 Retard is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur

4.8 Undesirable effects

Avaprop 160 Retard 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.

Common (1-9.9%)

General: Fatigue and/or lassitude (often transient)

Cardiovascular: Bradycardia, cold extremities, Raynaud's phenomenon.

CNS: Sleep disturbances, nightmares, insomnia,

Uncommon (0.1-0.9%)

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

Rare (0.01-0.09%)

General: Dizziness.

Blood: Thrombocytopaenia, blood dyscrasias,

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, memory loss.

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 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.

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-blocker should be gradual. In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted

If these symptoms are not attributed to some other cause, Avaprop 160 Retard should be withdrawn.

Bradycardia and hypotension are usually a sign of overdosage but may rarely be due to intolerance of the drug in which case it should be withdrawn.

4.9 Overdose

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 1-2 mg I.V. atropine and/or a cardiac pacemaker. If necessary this may be followed by a bolus dose of glucagon 10 mg I.V. This may be repeated if necessary or followed by an intravenous infusion of glucagon 1-10 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Propranolol is a competitive blocker 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 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-blockers, 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.

5.2 Pharmacokinetic properties

Avaprop 160 Retard is a modified release preparations designed to release propranolol over a period of time. During a pharmacokinetic study in volunteers it was found that the average time to reach maximum plasma concentration was 5 to 6 hours and the mean peak plasma concentration was found to be 35.38 ng/ml.

Following oral dosing with the sustained release preparation of propranolol, the blood profile is flatter than after conventional 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 bound to plasma proteins. Propranolol is almost completely absorbed from the gastro-intestinal tract. It is metabolised in the liver and its metabotes are excreted in urine with very small amounts of unchanged drug.

5.3 Preclinical safety data

Propranolol is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in this Summary of Product Characteristics

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose, corn starch, shellac, talc. Capsule shells: titanium dioxide (E171), erythrosine (E127) and gelatin.

6.2 Incompatibilities

Not known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store at or below 25°C in a dry place and protected form light.

6.5 Nature and contents of container

Capsule container, i.e.: polypropylene securitainer with polyethylene closure. Number of capsules per container: 28, 30, 56, 60 or 100.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Rd,

Eaton Socon St Neots

Cambridgeshire PE19 8ET UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0459

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/05/1997 / 17/03/2003

10    DATE OF REVISION OF THE TEXT

23/05/2011