SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Inderal LA 160mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Propranolol hydrochloride Ph Eur 160 mg

3 PHARMACEUTICAL FORM

Pink/lavender or white opaque capsules containing propranolol hydrochloride in a controlled release formulation.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

a)    Control of hypertension

b)    Management of angina

c)    Prophylaxis of migraine

d)    Management of essential tremor

e)    Management of anxiety

f)    Adjunctive management of thyrotoxicosis

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

Posology and method of administration

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

Adults

Hypertension: The usual starting dose is one 160 mg Inderal LA 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 80 mg Half-Inderal LA increments until an adequate response is achieved. A further reduction in blood pressure can be obtained if a diuretic or other antihypertensive agent is given in addition to Inderal LA and Half-Inderal LA.

Angina, anxiety, essential tremor, thyrotoxicosis and the prophylaxis of migraine: One Half-Inderal LA capsule daily, taken either morning or evening, may be sufficient to provide adequate control in many patients. If necessary the dose may be increased to one Inderal LA capsule per day and an additional Half-Inderal LA increment may be given.

Portal hypertension: Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosing should begin with one 80 mg Half-Inderal LA capsule daily, increasing to one 160 mg Inderal LA capsule daily depending on heart rate response. Further 80 mg Half-Inderal LA increments may be added up to a maximum dose of 320 mg once daily.

Patients who are already established on equivalent daily doses of Inderal tablets should be transferred to the equivalent doses of Half-Inderal LA or Inderal LA daily, taken either morning or evening.

Children

Inderal LA and Half-Inderal LA are not intended for use in children.

Elderly Patients

Evidence concerning the relation between blood level and age is conflicting.

It is suggested that treatment should start with one Half-Inderal LA capsule once daily. The dose may be increased to one Inderal LA capsule daily or higher as appropriate.

4.3 Contraindications

Inderal LA and Half-Inderal LA must not be used if there is a history of bronchial asthma or bronchospasm. The product label states the following warning: “Do not take Inderal LA 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 beta₂ 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 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.

Inderal LA and Half-Inderal LA, 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.

Inderal LA and Half-Inderal LA 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

Inderal LA and Half-Inderal LA as with other beta-blockers:

•    although contra-indicated in uncontrolled heart failure (see Section 4.3) may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.

•    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). Inderal LA and Half-Inderal LA occasionally causes hypoglycaemia, even in non-diabetic patients, e.g., elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with Inderal LA and Half-Inderal LA has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of Inderal LA and Half-Inderal LA and hypoglycaemic therapy in diabetic patients.

Inderal LA and Half-Inderal LA 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.

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 Inderal LA 80mg. 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.

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.

Inderal LA and Half-Inderal LA must be used with caution in patients with decompensated cirrhosis. (see section 4.2)

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).

Interference with laboratory tests: Inderal LA and Half-Inderal LA 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.

Interaction with other medicinal products and other forms of interaction

Inderal LA and Half-Inderal LA modify the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Inderal LA or Half-Inderal LA and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.(see section 4.3 and 4.4).

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.

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-blockers, may increase atrioventricular 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 sinoatrial or atrio-ventricular 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 Inderal LA and Half-Inderal LA. 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, Inderal LA and Half-Inderal LA should not be given during pregnancy unless their use is essential. There is no evidence of teratogenicity with Inderal. 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 Inderal LA or Half-Inderal LA 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

Inderal LA and Half-Inderal LA 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.

Uncommon (0.1-0.9%)

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

Rare (0.01-0.09%)

General: Dizziness.

Blood: Thrombocytopaenia.

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.

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 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.

5.1 Pharmacodynamic properties

Propranolol is a competitive antagonist at both betai 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

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 Inderal 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%).

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.

6.1 List of excipients

Erythrosine (E127)

Ethyl cellulose Ph Eur. (E462)

Gelatin Ph Eur. (E441)

Glycerol Ph Eur. (E422)

Iron oxide, red (E172)

Iron oxide, black (E172) Methylhydroxypropylcellulose Ph Eur. (E464) Microcrystalline cellulose Ph Eur. (E460) Titanium dioxide Ph Eur. (E171)

6.2 Incompatibilities

None known.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Store below 25°C, protected from light and moisture.

6.5    Nature and contents of container

Patient calendar pack of 28 capsules.

6.6 Special precautions for disposal

Use as directed by the prescriber.

7 MARKETING AUTHORISATION HOLDER

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17901/0019

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11^th June 2000

10 DATE OF REVISION OF THE TEXT

20/01/2011