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Injection solution containing Propranolol hydrochloride BP. 1 mg per 1 mL in printed glass ampoules of 1 mL. Inactive ingredients are citric acid and water.
Propranolol is a competitive antagonist at both the beta1 and beta2-adrenoreceptors. It has no agonist activity at the beta-adrenoreceptor but has membrane stabilising activity at concentrations exceeding 1 to 3 mg/L. Competitive beta-adrenoreceptor 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-adrenoreceptor blocking medicines, 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 Afro-Caribbean black patients.
Following intravenous administration the plasma half-life of propranolol is about 2 hours and the ratio of metabolites to parent medicine in the blood is lower than after oral administration. In particular 4-hydroxy propranolol is not present after intravenous administration.
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%). The liver removes up to 90% of an oral dose with an elimination half-life of 3-6 hours.
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.
For the emergency treatment of cardiac dysrhythmias and thyrotoxic crisis only.
The initial dose of INDERAL is 1 mg (1 mL) injected over one minute. This may be repeated at two-minute intervals until a response is observed or to a maximum dose of 10 mg in conscious patients or 5 mg in patients under anaesthesia.
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.
Dosage should be individually determined and the following is only a guide.
0.025 to 0.05 mg/kg injected slowly under ECG control and repeated three or four times daily as required.
INDERAL must not be used if there is a history of bronchial asthma or bronchospasm.
INDERAL as with other beta-adrenoreceptor blocking medicines must not be used in patients with any of the following:
INDERAL must not be used in patients prone to hypoglycaemia ie. Patients after prolonged fasting or patients with restricted counter-regulatory reserves.
Special care should be taken with patients whose cardiac reserve is poor. Beta-adrenoreceptor blocking medicines should be avoided in uncontrolled heart failure (see CONTRAINDICATIONS). However, they may be used in patients whose signs of failure have been controlled.
INDERAL is contraindicated in severe peripheral arterial circulatory disturbances and may also aggravate less severe peripheral arterial circulatory disturbances.
Due to its negative effect on conduction time, caution must be exercised if INDERAL is given to patients with first degree heart block.
INDERAL modifies the tachycardia of hypoglycaemia. INDERAL occasionally causes hypoglycaemia, even in non-diabetic patients, eg. Neonates, infants, children, elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with INDERAL has rarely presented with seizures and/or coma in isolated patients. Caution should be exercised in the concurrent use of INDERAL and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.
INDERAL may mask the signs of thyrotoxicosis.
One of the pharmacological actions of beta-adrenoreceptor blocking medicines is to reduce heart rate. In the rare instance when symptoms may be attributable to the slow heart rate, the dose may be reduced.
INDERAL 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. INDERAL may increase the risk of hepatic encephalopathy.
Caution must be exercised when using anaesthetic agents with INDERAL. Use of beta-adrenoreceptor blocking medicines with anaesthetic medicines may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.
As with all other medicines, INDERAL should not be given in pregnancy unless its use is essential. There is no evidence of teratogenicity with INDERAL. However, beta-adrenoreceptor blocking medicines 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.
Most beta-adrenoreceptor blocking medicines, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.
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.
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 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and INTERACTIONS)
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 CONTRAINDICATIONS).
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 the rare event of intolerance, manifested as bradycardia and hypotension, the medicine should be withdrawn and, if necessary, treatment for overdosage instituted.
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. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).
Care must be exercised in prescribing a beta-adrenoreceptor blocking medicine with Class I antidysrhythmic agents such as disopyramide.
Digitalis glycosides in association with beta-adrenoreceptor blocking medicines may increase atrioventricular conduction time.
Combined use of beta-adrenoreceptor blocking medicines 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 SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-adrenoreceptor blocking medicine nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
Concomitant therapy with dihydropyridines 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-adrenoreceptor blocking medicines. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta-adrenoreceptor blocking medicines as, in rare cases, vasoconstriction, hypertension and bradycardia may result.
Administration of propranolol during infusion of lignocaine may increase the plasma concentration of lignocaine by about 30%. Patients already receiving propranolol 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-adrenoreceptor blocking medicines may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two medicines are co-administered, the beta-adrenoreceptor blocking medicine should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenoreceptor blocking medicine therapy, the introduction of beta-adrenoreceptor blocking medicine should be delayed for several days after clonidine administration has stopped (also see prescribing information for clonidine).
Caution is necessary 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 medicines e.g. ibuprofen and indomethacin, may decrease the hypotensive effects of propranolol.
Concomitant administration of propranolol and chlorpromazine may result in an increase in plasma levels of both medicines. 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 the concomitant therapy with dihydropyridine calcium channel blockers).
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 medicine 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-adrenoreceptor stimulant such as dobutamine 2.5 to 10 mg/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-adrenoreceptor 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 can usually be reversed by beta-2 agonist bronchodilators such as salbutamol; large doses may be required and the dose should be titrated according to the clinical response. Oxygen or artificial ventilation may be required in some cases.
Store below 30°C, protected from light.
60 months
Prescription Medicine.
10 x 1 mL ampoules.
INDERAL injection is compatible with 0.9% w/v sodium chloride and 5% w/v dextrose.
AstraZeneca Limited
303 Manukau Rd, Epsom
PO Box 1301
Auckland
Telephone (09) 623 6300
3 April 2001
CDS 201000