INFORMATION FOR HEALTH PROFESSIONALS
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APO-PROPRANOLOL 10 mg tablets are round, 6.5 mm in diameter, biconvex with a breakline and coated pink. Each tablet contains 10 mg propanolol hydrochloride and typically weighs 99 mg.
APO PROPRANOLOL 40 mg tablets are round, 8.7 mm in diameter, biconvex with a breakline and coated pink. Each tablet contains 40 mg propanolol hydrochloride and typically weighs 197 mg.
Propranolol is a β-andrenoreceptor blocking agent which is structurally related to other beta-blocking agents such as atenolol, pindolol and oxprenolol, differing from these compounds by substitution on the aromatic ring. Propranolol is a competitive antagonist at both the beta1 and beta2-adrenoreceptors. It has little intrinsic sympathomimetic activity. It has some membrane stabilising effect at concentrations exceeding 1-3mg/L, although such concentrations are rarely achieved during oral therapy. Competitive beta-andrenoreceptor blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta-antagonists such as isoprenaline.
As with other beta-andrenoreceptor blocking medicines, propranolol has negative intropic effects and is therefore contraindicated in congestive heart failure.
APO-PROPRANOLOL is a racemic mixture and the active form is the S (-) isomer of propanolol. 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.
The most important effect of propranolol hydrochloride is to reduce the influence of excessive sympathetic nervous stimulation on the heart. Pulse rate, force of cardiac contraction and cardiac output are all reduced, resulting in a significant reduction in myocardial oxygen demand, greater than the reduction in work. These effects singly or in combination, are of therapeutic value in several cardiovascular diseases. APO-PROPRANOLOL reduces elevated blood pressure by an unknown mechanism. The drug also inhibits exercise induced tachycardia and this effect is related to plasma concentration. No correlation has been found between the plasma concentration and its antihypertensive effect.
The possible mechanism of the antianginal activity of propranolol hydrochloride appears to be due to a reduction in the left ventricular work and oxygen utilisation resulting from inhibition or cardiac sympathetic nerve stimulation. Serotonin antagonism has been demonstrated with propranolol hydrochloride. The therapeutic benefit of this property in centrally medicated disorders is uncertain.
Propranolol hydrochloride is rapidly and almost completely absorbed from the intestine. A large part of the absorbed drug is lost to the systemic circulation due to the first pass metabolism in the liver. After repeated administration, the first pass removal process becomes saturated and, at steady state, the plasma concentration is proportional to the dose, although there is some variation between patients as to the blood levels achieved at a given dose. In addition, correlation of plasma level to therapeutic effect varies considerably with propranolol hydrochloride as with some other beta-blockers. This lack of correlation is most marked in the treatment of angina and hypertension.
Peak blood levels occur between 1-3 hours after oral administration and will have an average value of 0.1mcg/ml per 80mg single dose. With chronic administration the mean plasma half-life is from 3-6 hours, determined by clearance and plasma binding. The pharmacological effect lasts much longer.
Propranolol is absorbed from circulation and is widely distributed throughout the body tissues. Approximately 93% is bound to serum proteins in humans.
Propranolol hydrochloride is rapidly and extensively metabolised and excreted by the liver. Hydroxylation of the aromatic nucleus occurs with degradation of the isoprenaline side chain. Over 20 metabolites have been identified. One of these (4-hydroxypropranolol) found only after oral administration, has beta-adrenergic blocking properties.
Some 95-100% of a dose of propranolol hydrochloride is excreted as metabolites and their conjugates in the urine. Small amounts of unchanged propranolol are also excreted in the urine.
Propranolol hydrochloride has a variable bioavailability due to an avid hepatic binding mechanism. The first-pass effect varies from patient to patient and will determine the drug plasma concentration. A good estimation of beta-blockade and bioavailability can be clinically gauged by checking for reduction in standing or exercise heart rate. This also gives a simple guide to compliance.
Hypertension: A starting dose of 80 mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160-320 mg per day. With concurrent diuretic or other anti-hypertensive drugs a further reduction of blood pressure is obtained.
Angina, Anxiety, 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 anxiety, migraine and essential tremor is usually seen in the range 80-160 mg/day and in angina in the range 120-240 mg/day.
Dysrhythmias, Anxiety Tachycardia, Hypertrophic Obstructive Cardiomyopathy and Thyrotoxicosis: A dosage range of 10-40mg three to four times a day usually achieves the required response.
Post Myocardial Infarction: Treatment should start 5-21 days after myocardial infarction, with an initial dose of 40mg four times a day for 2-3 days. In order to improve compliance the total daily dose can thereafter be given as 80mg twice a day.
Phaeochromocytoma: (To be used only with an alpha-adrenoreceptor blocking medicine).
Pre-operative: 60mg daily for 3 days is recommended.
Non-operative malignant cases: 30mg daily.
Evidence concerning the relationship between the blood levels and age is conflicting. With regard to the elderly, the optimum dose should be individually determined according to clinical response.
The dose of APO-PROPRANOLOL should always be individually determined. The following doses are intended only as a guide.
Dysrhythmias, Phaeochromocytoma and Thyrotoxicosis: 0.25-0.5mg/kg three or four times daily as required.
Migraine: Under age of 12: 20mg two or three times daily. Over age of 12: The adult dose.
Cardiac Failure: Beta-blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history of cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy as may occur in chronic alcoholism. In patients without a history of cardiac failure, continuing depression of the myocardium may lead to cardiac failure. If signs of cardiac failure are present the patient should be fully digitalised and/or given an angiotensin converting enzyme (ACE) inhibitor or vasodilators with or without a diuretic and carefully monitored. If cardiac failure persists, the beta-blocker should be withdrawn.
Heart Rate: One of the pharmacological actions of beta-adrenoceptor blocking medicines is to reduce heart rate. In the rare instance when the symptoms may be attributable to the slow heart rate the dose may be reduced.
Peripheral Circulation: Propranolol may aggravate peripheral circulatory disorders.
History of Anaphylactic Reaction: While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge. Some patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reaction.
Anaesthesia: It may be decided to discontinue therapy with beta-adrenoceptor blocking agents before surgery, in which case a gradual withdrawal is recommended. If it is decided not to discontinue therapy with beta-adrenoceptor blocking agents before surgery, care should be taken when using anaesthetic agents with propranolol. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible.
Asthma/Bronchospasm: Beta-andrenergic blockade of the smooth muscle of the bronchi and bronchioles results in increased airway resistance. Fatality could occur.
Concomitant Therapy with Calcium Antagonists: The concomitant use of beta-blockers and calcium antagonists with myocardial depressant and sinus node activity (e.g. verapamil and to a lesser extent diltizem) may cause hypotension, bradycardia and asystole. This is particularly so in patients with impaired ventricular function and/or sinoatrial or artioventricular conduction abnormalities. The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiously with beta-blockers. If excessive hypotension develops the calcium antagonist should be stopped or the dosage reduced.
Euthyroid hyperthyroxinaemia: The effects of beta-blockers on thyroid hormone metabolism may result in elevations of serum free thyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism, additional investigation is necessary before a diagnosis of thyrotoxicosis can be made.
Lignocaine: Patients already receiving propranolol tend to have higher lignocaine levels. Administration of propranolol during infusion of lignocaine may increase plasma concentrations by about 30%. This combination should be avoided.
First degree Heart Block: Due to its negative effect on conduction time, caution must be exercised if APO-PROPRANOLOL is given to patients with first degree heart block.
Antiarrhythmic Drugs: Care should be taken when prescribing beta-blockers with antiarrhythmic drugs. Interactions have been reported during concomitant β-blocker therapy with the class 1A agents disopyramide and less frequently quinidine, the class 1B agents tocainide, mexiletine and lignocaine, the class 1C agents flecainide and propafenone, the class III agentamiodarone and the class IV antiarrhythmic agents.
Prinzmetal Angina: There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a beta-blocker. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.
Diabetes: Beta-blockers affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
Use of Catecholamine Depleting Agents: Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect to beta-blockade may produce an excessive reduction of the resting sympathetic nervous tone.
Clonidine: Concurrent use of beta-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker. If replacing clonidine with beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
Phaeochromocytoma: An alpha-blocking drug (e.g. phentolamine, phenoxybenzamine) should be administered before the beta-blocker to avoid exacerbation of hypertension.
Ocular and Dermatological Reactions: Various skin rashes and conjunctival xerosis have been reported with beta-blockers. Cross reactions may occur between beta-blockers , therefore substitutions within the group may not necessarily preclude occurrence of symptoms.
Allergic Conditions: These may be exaggerated by beta-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). Beta-blockers should be avoided if there is a risk of bronchospasm.
Hyperthyroidism: Beta-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid hormone status, special care should be exercised in those patients who are hyperthyroid and are also receiving beta-blockers.
Care should be taken if beta-blockers have to be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias have occurred following abrupt discontinuation of beta-blockade in patients with ischaemic heart disease. Therefore, it is recommended that the dosage be reduced gradually over a period of 8-14 days during which time the patients progress should be assessed. The drug may be temporarily reinstituted if the angina worsens. If the drug must be withdrawn abruptly, close observation is required. In the perioperative period, beta-blockers should not be withdrawn unless indicated.
Patients with angina should be warned against abrupt withdrawal of the drug and of the need to ensure supplies do not run out.
Use of APO-PROPRANOLOL is unlikely to result in any impairment of the patients ability to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.
Since the half life may be increased in patients with significant renal impairment, caution must be exercised when starting treatment and selecting the initial dose. In patients with severe renal disease, haemodynamic changes following beta-blockade may impair renal function further. Beta-blockers that are excreted mainly by the kidney may require dose adjustment in patients with renal failure.
Since the half-life may be increased in patients with significant hepatic impairment, care should be taken when starting treatment and selecting initial dose.
Decompensated Cirrhosis: Propranolol should be used with caution in decompensated cirrhosis.
Portal Hypertension: In patients with portal hypertension, hepatic function will deteriorate and hepatic encephalopathy may develop. APO-PROPRANOLOL may increase the risk of hepatic encephalopathy.
Category C.
As with all other medicines, propranolol should not be given in pregnancy unless its use is essential. Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.
There is no evidence of teratogenicity with propranolol.
Perinatal complications, such as a small placenta and intrauterine growth retardation, have been reported in a few cases where the mother took propanolol hydrochloride during pregnancy. Some infants born to mothers treated with propranolol hydrochloride were reported to have hypoglycaemia and/or bradycardia. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.
Beta-adrenergic blocking agents may cause pharmacological effects such as bradycardia in the foetus and newborn infant. During the final part of pregnancy and parturition these drugs should only be given after weighing the needs of the mother against the risk to the foetus.
Most beta-adrenoreceptors 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.
APO-PROPRANOLOL is usually well tolerated and side effects are usually transient in nature, rarely necessitating withdrawal of the treatment. The most serious adverse effects encountered are congestive heart failure and bronchospasm in susceptible patients.
Gastrointestinal disturbances (anorexia, nausea, vomiting, diarrhoea, abdominal pain) are the most common adverse effects reported. Other less frequently reported adverse reactions are cold extremities and exacerbation of Raynaud's phenomenon, congestive heart failure, sleep disturbances including vivid dreams, dizziness, fatigue and bronchospasm. Rare cases of thrombocytopenia and purpura have been reported. Bradycardia and CNS symptoms including mood changes and hallucinations have been reported rarely.
Gastrointestinal: Gastrointestinal disturbances including nausea, vomiting, flatulence and diarrhoea.
Haematological: Reduction of platelet adhesiveness, thrombocytopenia purpura, nonthrombocytopenia purpura, agranulocytosis, eosinophilia. An increase in antinuclear antibodies (ANA) has been observed, but the clinical relevance is not clear.
Cardiovascular: Bradycardia, hypotension, exacerbation of intermittent claudication, congestive heart failure, deterioration of previously controlled heart failure, postural hypotension which may be associated with syncope, cold extremities, paraesthesia of the hands, Raynaud's phenomenon and precipitation of heart block.
Central Nervous System: Lassitude, insomnia, nightmares, hallucinations, psychiatric complications (depression, psychoses, psychotic reactions and acute confusional states) and mood changes.
Endocrine: Isolated reports of impotence have been recorded. Rare cases of hypoglycaemia in children have been reported.
Respiratory: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcomes. Also respiratory distress and laryngospasm.
Neurological: Paraesthesia.
Integumentary: Purpura, erythematous rash, exacerbation of psoriasis, psoriasiform skin reactions, alopecia, dry eyes, skin rashes and conjunctival xerosis.
Special senses: Visual disturbances, diminished vision, rarely diminution and loss of hearing.
Other: Fatigue, loss of libido, tinnitus, conjunctivitis, pharyngitis, fever combined with aching and sore throat, urinary retention associated with repeated bouts of paroxysmal tachycardia and flushing of the face. Isolated reports of myasthenia gravis-like syndrome or exacerbation of myasthenia gravis have been reported.
APO-PROPRANOLOL discontinuation 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 beta-blocker should be withdrawn and, if necessary treatment for overdosage instituted.
Care should be taken in prescribing a beta-adrenoceptor blocking medicine with a Class 1 antidysrhythmic agent such as disopyramide.
Care should be taken in the parenteral administration of preparations containing adrenaline to patients taking beta-adrenoceptor blocking medicines as, in rare cases, vasoconstriction, hypertension and bradycardia may result.
Beta-adrenoceptor blocking medicines should be used with caution in combination with verapamil in patients with impaired ventricular function. The combination should not be given to patients with conduction abnormalities. Neither medicine should be administered intravenously with 48 hours of discontinuing the other.
Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time.
Concomitant use of cimetidine or hydralazine will increase, whereas concomitant use of alcohol will decrease, the plasma levels of propanolol.
Care should be taken when using propranolol with ergotamine, dihydroergotamine or related compounds since vasopastic reactions have been reported in a few patients.
The hypotensive effects of beta-blockers may be decreased when used concomitantly with prostaglandin synthetase inhibiting drugs, e.g. ibuprofen and indomethacin.
Concomitant administration of propranolol and chloropromazine 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.
Pharmacokinetic studies have shown that the following agents may interact with propranolol due to effects on the enzyme systems in the liver which metabolise propranolol and these agents: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers e.g. nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed to be made according to clinical judgement. See also Warnings and Precautions, Concomitant therapy with Calcium Antagonists, for information concerning concomitant therapy with dihydropyridine calcium channel blockers.
See also Warnings and Precautions for information on calcium antagonists, diabetes, antiarrhythmic drugs, lignocaine, anaesthesia and the perioperative period, catecholamine depleting agents and clonidine.
The common signs to be expected in overdosage are bradycardia, hypotension, bronchospasm or acute cardiac failure.
If overdosage occurs, in all cases therapy with APO-PROPRANOLOL should be discontinued and the patient observed closely. In addition the following therapeutic measures are suggested.
General treatment should include: close supervision in a monitored environment (which may include 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 intravenous fluids to treat hypotension and shock.
Excessive bradycardia can be countered with atropine 1 to 2 mg intravenously (incrementally in 0.6mg doses) 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 isoprenaline (25 mcg initially) or orciprenaline (0.5 mg) may be given by slow intravenous injection, or dobutamine (2.5-10mcg/kg/min) by intravenous infusion may be given.
Cardiac Failure: Digitalisation and diuretics.
Hypotension: Vasopressors, e.g. noradrenaline or adrenaline (there is evidence that adrenaline is the drug of choice).
Bronchospasm: Bronchospasm can usually be reversed by beta-bronchodilators such as salbutamol. Large doses may be required and the dose should be titrated according to clinical response. Oxygen or artificial ventilation may be required in some cases.
Store below 30°C.
Protect form heat, light and moisture.
Keep container tightly closed.
Prescription-Only medicine.
APO-PROPRANOLOL 10 mg tablets
Bottles of 50 and 500 tablets
APO-PROPRANOLOL 40 mg tablets
Bottles of 50 and 500 tablets
Tablets contain lactose and cornflour (non-sensitising glutens) and colouring agents.
APOTEX NZ LTD
32 Hillside Road
Glenfield
Private Bag 102995
North Shore Mail Centre
Auckland
Tel: (09) 444 2073
Fax: (09) 444 2951
24 June 1999