1. Name Of The Medicinal Product
Inderal Tablets 80 mg.
2. Qualitative And Quantitative Composition
Propranolol Hydrochloride Ph. Eur. 80 mg.
3. Pharmaceutical Form
Round pink film coated tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
a) the control of hypertension;
b) the management of angina pectoris;
c) long term management against re-infarction after recovery from acute myocardial infarction;
d) the control of most forms of cardiac dysrhythmias;
e) the prophylaxis of migraine;
f) the management of essential tremor;
g) relief of situational anxiety and generalised anxiety symptoms, particularly those of somatic type;
h) prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices;
i) the adjunctive management of thyrotoxicosis and thyrotoxic crisis;
j) management of hypertrophic obstructive cardiomyopathy;
k) management of phaeochromocytoma peri-operatively (with an alpha-blocker).
4.2 Posology And Method Of Administration
For oral administration
Adults
Hypertension
A starting dose of 80 mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160 to 320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
Angina, migraine and essential tremor
A starting dose of 40 mg two or three times daily may be 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 to 160 mg/day and in angina in the range 120 to 240 mg/day.
Situational and generalised anxiety
A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately to 40 mg twice daily which, in individual cases, may be increased to 40 mg three times daily. Treatment should be continued according to response. Patients should be reviewed after 6 to 12 months treatment.
Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis
A dosge range of 10 to 40 mg three or four times a day usually achieves the required response.
Post myocardial infarction
Treatment should start between days 5 and 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily dosage may thereafter be given as 80 mg twice a day.
Portal hypertension
Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosage should begin with 40 mg twice daily, increasing to 80 mg twice daily depending on heart rate response. If necessary, the dose may be increased incrementally to a maximum of 160 mg twice daily.
Phaechromocytoma
(Used only with an alpha-receptor blocking drug).
Pre-operative: 60 mg daily for 3 days is recommended. Non-operable malignant cases: 30 mg daily.
Elderly
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
Dysrhythmias, phaeochromocytoma, thyrotoxicosis
Dosage should be individually determined and the following is only a guide:
Oral: 0.25 to 0.5 mg/kg three or four times daily as required.
Migraine
Oral: Under the age of 12: 20 mg two or three times daily.
Over the age of 12: The adult dose.
Fallot's tetralogy
The value of Inderal in this condition is confined mainly to the relief of right-ventricular outflow tract shut-down. It is also useful for treatment of associated dysrhythmias and angina. Dosage should be individually determined and the following is only a guide:
Oral: Up to 1 mg/kg repeated three or four times daily as required.
4.3 Contraindications
Inderal must not be used if there is a history of bronchial asthma or bronchospasm. The product label states the following warning: “Do not use Inderal 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 as with other beta-adrenoceptor blocking drugs must not be used in patients with any of the following: 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; Prinzmetal's angina.
4.4 Special Warnings And Precautions For Use
Inderal as with other beta-adrenoceptor blocking drugs:
- although contraindicated 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.
- although contraindicated 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 modify the tachycardia of hypoglycaemia (see Section 4.5).
- may mask the signs of thyrotoxicosis.
- will reduce heart rate as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced.
- should not be discontinued abruptly in patients suffering from ischaemic heart disease. Either the equivalent dosage of another beta-adrenoceptor blocking drug may be substituted or the withdrawal of Inderal should be gradual.
- 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.
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 must be used with caution in patients with decompensated cirrhosis.
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.
Interference with laboratory tests. Inderal 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Inderal modifies the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Inderal and hypoglycaemic therapy in diabetic patients. Inderal may prolong the hypoglycaemic response to insulin.
Caution must be exercised in prescribing a beta-adrenoceptor blocking drug with Class I antiarrhythmic agents such as disopyramide.
Digitalis glycosides in association with beta-adrenoceptor blocking drugs may increase atrioventricular conduction time.
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 SA or AV 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, 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-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.
Administration of Inderal during infusion of lignocaine may increase the plasma concentration of lignocaine by approximately 30%. Patients already receiving Inderal tend to have higher lignocaine levels than controls. The combination should be avoided.
Concomitant use of cimetidine or hydralazine will increase, whereas concomitant use of alcohol will decrease, 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-adrenoceptor 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 Inderal since vasospastic reactions have been reported in a few patients.
Concomitant use of prostaglandin synthetase inhibiting drugs eg, ibuprofen and indomethacin, may decrease the hypotensive effects of Inderal.
Concomitant administration of Inderal 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 Inderal.
Caution must be exercised when using anaesthetic agents with Inderal. The anaesthetist should be informed and the choice of anaesthetic should be an 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 the concomitant therapy with dihydropyridine calcium channel blockers).
4.6 Pregnancy And Lactation
Pregnancy
As with all drugs Inderal should not be given during pregnancy unless its use is essential. There is no evidence of teratogenicity with Inderal. 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
Use 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 is 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 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.
Endocrine: hypoglycaemia in children.
Gastrointestinal: gastrointestinal disturbance.
Haematological: purpura; thrombocytopenia.
Integumentary: alopecia; dry eyes; psoriasiform skin reactions; exacerbation of psoriasis; skin rashes.
Neurological: paraesthesia.
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.
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.
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-adrenoceptor 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
Inderal 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 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 contraindicated in uncontrolled heart failure.
Inderal 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 ancillary properties possessed by R (+) propranolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.
Inderal is effective and well tolerated in most ethnic populations, 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 fasting 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
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
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6.2 Incompatibilities
None known.
6.3 Shelf Life
5 years.
6.4 Special Precautions For Storage
Store below 30°C, protected from light and moisture.
6.5 Nature And Contents Of Container
HDPE bottles of 60 tablets.
6.6 Special Precautions For Disposal And Other Handling
None stated.
7. Marketing Authorisation Holder
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8. Marketing Authorisation Number(S)
PL 17901/0023.
9. Date Of First Authorisation/Renewal Of The Authorisation
11.06.00
10. Date Of Revision Of The Text
11th June 2000
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