Propranolol 80mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Propranolol 80mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Propranolol Hydrochloride B.P. 80mg.
3 PHARMACEUTICAL FORM
Pink, film-coated tablets, face I embossed 'P/80', face II embossed 'a' intended for oral administration to human beings.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. ) The control of hypertension.
2. ) The management of angina pectoris.
3. ) The long term prophylaxis after recovery from acute myocardial
infarction.
4. ) The control of most forms of cardiac dysrhythmias.
5. ) The prophylaxis of migraine.
6. ) The management of essential tremor.
7. ) Relief of situational anxiety and generalised anxiety symptoms,
particularly those of somatic type.
8. ) Prophylaxis of upper gastro-intestinal bleeding in patients with portal
hypertension and oesophageal varices.
9. ) The adjunctive management of thyrotoxicosis and thyrotoxic crisis.
10. ) Management of hypertrophic obstructive cardiomyopathy.
11. ) Management of phaeochromocytoma peri operatively (with an alpha
blocker).
4.2 Posology and method of administration
Adults:
Hypertension: A starting dose of 80mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160 - 320mg per day. Lower doses may be effective when a diuretic or other antihypertensive drugs are given concurrently.
Angina, migraine and essential tremor: Initially, 40mg two or three times daily, 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 - 160mg/day and in angina in the range 120 - 240mg/day.
Situational and generalised anxiety: In acute situational anxiety, a dose of 40mg daily may provide short term relief. In generalised anxiety requiring longer term therapy, an adequate response may be expected with 40mg twice daily which, in individual cases, may be increased to 40mg three times daily. Treatment should be continued according to response and patients should be reviewed after six to twelve months’ treatment.
Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: 10 - 40mg three or four times a day.
Post myocardial infarction: For long-term prevention of sudden cardiac death in patients who have survived the acute phase of a myocardial infarct, treatment should start between days 5 and 21 after myocardial infarction, with an initial dose of 40mg four times a day for 2 or 3 days. In order to improve compliance, the total daily dosage may thereafter be given as 80mg twice a day.
Portal hypertension: Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Initially, 40mg twice daily, increasing to 80mg twice daily depending on heart rate response. If necessary, the dosage may be increased incrementally to a maximum of 160mg twice daily.
Phaeochromocytoma: Propranolol should be used only with an alpha-receptor blocking drug). Pre-operative: 60mg daily for three days. Non-operable malignant cases: 30mg daily.
Children: Dysrhythmias, phaeochromocytoma, thyrotoxicosis. Dosage should be determined individually. The following dosages are intended only as a guide: 0.25 - 0.5mg/kg three or four times daily as required.
Migraine: Under the age of 12: 20mg two or three times daily.
Over the age of 12: the adult dose.
Fallot's Tetralogy: Propranolol is used mainly to relieve 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: Up to 1mg/kg repeated three or four times daily as required.
Elderly patients: The optimum dose should be individually determined according to clinical response.
4.3 Contraindications
Hypersensitivity to propranolol or to any of the excipients; the presence of second or third degree heart block; cardiogenic shock; a history of bronchospasm or bronchial asthma, chronic obstructive airways disease; after prolonged fasting (ie hypoglycaemia); in metabolic acidosis (eg in diabetes); bradycardia(heart rate <45-50 beats/min); hypotension; severe peripheral arterial disturbances; sick sinus syndrome; Prinzmetal's angina; untreated phaeochromocytoma. Its use may lead to hypertensive crisis.
The product labelling and patient information leaflet will include a suitable warning regarding taking the medicine with a history of wheezing or asthma.
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.
4.4 Special warnings and precautions for use
One of the pharmacological actions of propranolol is to reduce the heart rate; in the instance when symptoms may be attributable to slow heart rate, the dose may be reduced.
Special care should be taken with patients whose cardiac reserve is poor. Beta-adrenoceptor blocking drugs should be avoided in overt heart failure; however, they may be used in patients whose signs of failure have been controlled.
Caution must be exercised if propranolol is given to patients with first degree heart block.
Heart failure due to thyrotoxicosis often responds to propranolol alone, but if other adverse factors co-exist myocardial contractility must be maintained and signs of failure controlled with digitalis and diuretics. Propranolol may mask the important signs of thyrotoxicosis and hyperthyroidism.
As with other beta-adrenoceptor blocking agents, in patients with ischaemic heart disease, treatment should not be discontinued abruptly. Either the equivalent dosage of another beta-adrenoceptor blocker may be substituted or the withdrawal of propranolol should be gradual.
Since the half-life of propranolol may be increased in patients with significant hepatic or renal impairment, care should be taken when starting treatment and selecting the initial dose. Elderly patients should be treated with caution, starting with a lower dosage, although tolerance is usually good in the elderly.
Propranolol must be used with caution in patients with decompensated cirrhosis.
Liver function will deteriorate in patients with portal hypertension and hepatic encephalopathy may develop. There have been some reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy.
Although contraindicated in severe peripheral circulatory disturbances, beta adrenoreceptor blocking drugs may also aggravate less severe forms. Therefore, propranolol should be used with great caution in conditions such as Raynaud’s disease/syndrome or intermittent claudication.
Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported in patients administered propranolol.
Psoriasis may be aggravated by the use of beta adrenoreceptor blocking drugs.
Beta adrenoreceptor blocking drugs should not be used in untreated phaeochromocytoma (See section 4.3). However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.
Beta adrenoreceptor blocking drugs 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. Particular caution is necessarily, when beta adrenoceptor blocking drugs are used in patients with a history of anaphylaxis.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Withdrawal
Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. In the rare event of intolerance, manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted. The sudden withdrawal of beta-receptor antagonists may result in severe exacerbation of angina pectoris, acute myocardial infarction, sudden death, malignant tachycardia, sweating, palpitation and tremor. Withdrawal should be accomplished over 10 to 14 days however caution must be exercised as this does not always prevent rebound effects.
When withdrawing a beta-blocker in preparation for surgery, therapy should be discontinued for at least 24 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, although there may be an increased risk of hypertension. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs and the chosen anaesthetic should have as little negative inotropic activity as possible. The anaesthetist should always be informed about the use of a beta-blocking drug. The patient may be protected against vagal reactions by the intravenous administration of atropine.
Beta-blockers may increase the number and duration of anginal attacks in patients with Prinzmetal’s angina due to unopposed a-receptor mediated coronary artery vasoconstriction. Non-selective beta-blockers should not be used in these patients, and beta-1 selective blockers may be used only with the utmost care.
Propranolol may modify the tachycardia of hypoglycaemia and it may prolong the hypoglycaemic response to insulin. Propranolol 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 Propranolol has rarely presented with seizures and/or coma in isolated patients. Care should be exercised during the concomitant use of propranolol and hypoglycaemic therapy in patients with diabetes mellitus.
Beta-blocking drugs should be used with caution in combination with verapamil or diltiazem and the combination should not be given to 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.
Propranolol has been reported to interfere with some laboratory tests, viz. estimation of serum bilirubin by the diazo method and determination of catecholamines by fluorescence methods.
The label shall contain the following statement:
Do not use if you have a history of wheezing or asthma.
4.5 Interaction with other medicinal products and other forms of interaction
Adrenaline (epinephrine):
Care should be taken in the parenteral administration of preparations containing adrenaline (epinephrine) to patients taking beta- adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result.
Anaesthetics
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. Anaesthetic drugs causing myocardial depression, such as cyclopropane and trichlorethylene, are best avoided.
Anti-arrhythmics
Caution must be exercised in co-prescribing beta-adrenoceptor blockers with Class I anti-arrhythmic agents such as disopyramide, quinidine, flecainide and amiodarone may have potentiating effects on arterial conduction time and induce negative inotropic effect. 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
Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects eg verapamil, diltiazem can lead to prolongation of SA and AV conduction particularly in patients with impaired ventricular function or 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. Digitalis glycosides used in association with beta adrenoceptor blockers may increase AV conduction time.
Anticoagulants:
Propranolol may cause a reduction in clearance and an increase in plasma concentrations of warfarin.
Antidiabetic drugs
Propranolol modifies the tachycardia of hypoglycaemia; caution should therefore be exercised in the concomitant use of propranolol and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.
Antihypertensives:
Beta-adrenoceptor blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the drugs are coadministered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine with beta-adrenoceptor therapy, the introduction of the beta-adrenoceptor blocking drug should be delayed for several days after the clonidine administration has stopped. Concomitant use of moxonidine and beta blockers may result in an enhanced hypotensive effect. The steps for moxonidine withdrawal/introduction should be the same as for clonidine. Hypotensive effect may be enhanced when propranolol is taken with diuretics, methyldopa or levodopa.
Prazosin or other alpha-adrenoreceptor blockers may potentiate postural hypotension, tachycardia and palpitations.
Antimigraine drugs:
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. Propranolol inhibits the metabolism of rizatriptan which can significantly increases plasma concentration levels. A dose reduction to 5mg is recommended. Administration should be separated by 2 hours.
Barbiturates:
The metabolism of propranolol may be increased by potent liver enzyme inducer barbiturates.
Chlorpromazine:
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.
Cimetidine:
Concomitant use of cimetidine will increase, where as alcohol will decrease the plasma levels of propranolol.
Hydralazine:
Concomitant use of hydralazine will increase, where as alcohol will decrease the plasma levels of propranolol.
Imipramine:
Propranolol may cause plasma concentrations of imipramine to increase. Monamine-oxidase Inhibitors:
The hypotensive effects of beta-blockers may be enhanced by MAOIs. Non-steriodal anti-inflammatory drugs:
NSAIDs notably indometacin, may cause an increase in blood pressure. This may be particularly significant in patients with poorly controlled hypertension.
Rifampicin:
The metabolism of propranolol may be increased by potent liver enzyme inducer rifampicin.
Selective Serotonin Re-uptake Inhibitors:
Fluvoxamine inhibits oxidative metabolism and increases plasma concentrations of propranolol. This may result in severe bradycardia.
Theophylline:
Propranolol reduces the clearance and consequentially increases the plasma concentration of theophylline.
Tobacco:
Smoking tobacco may oppose the effects of beta blockers in the treatment of angina or hypotension. Patients should be encouraged to stop smoking, apart from its other toxic effects, it aggravates ocardial ischaemia, increases heart rate and can impair blood pressure control. If patient continues to smoke, dosage of the beta blocker may need to be increased or a cardio-selective beta blocker may be more appropriate.
Laboratory tests:
Interference with laboratory tests - Propranolol 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.
Dihydropyridine derivatives such as nifedipine (increased risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency).
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 Fertility, Pregnancy and lactation
Pregnancy
As with all drugs, Propranolol should not be given during pregnancy unless its use is essential. There is no evidence of teratogenicity with Propranolol. However, Beta adrenoceptor blocking drugs reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foerus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal 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 Propranolol is unlikely to result in any significant impairment of the ability of patients to drive or operate machinery. However, patients should be warned that visual disturbances, hallucinations, mental confusion, dizziness, drowsiness or fatigue may occur and they should not drive or operate machinery if they feel affected.
4.8 Undesirable effects
Very common ( ^ 1/10); common (s 1/100 to <1/10); uncommon 1/1,000 to <1/100); rare ( ^ 1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be estimated from the available data).
The following undesired events, listed by body system, have been reported.
Blood and lymphatic system disorders
Rare: thrombocytopenia
Frequency not known: agranulocytosis
Endocrine disorders
Frequency not known: masking signs of thyrotoxicosis Metabolic and nutritional disorders
Very rare: 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.
Frequency not known: changes in lipid metabolism (changes in blood concentrations of triglycerides and cholesterol)
Psychiatric disorders
Common : Sleep disturbances, nightmares.
Frequency not known: depression, confusion
Nervous system disorders
Rare: Hallucinations, psychoses, mood changes, confusion, memory loss, dizziness , paraesthesia.
Very rare: Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported.
Frequency not known: headache, seizure linked to hypoglycaemia.
Eye disorders
Rare: Dry eyes, visual disturbances.
Frequency not known: conjunctivitis Cardiac disorders Common: Bradycardia,
Rare: Heart failure deterioration, precipitation of heart block, postural hypotension, which may be associated with syncope,
Frequency not known: worsening of attacks of angina pectoris
Vascular disorders
Common: cold extremities, Raynaud's phenomenon.
Rare: exacerbation of intermittent claudication.
Respiratory thoracic and mediastinal disorders
Rare: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome.
Frequency not known: dyspnoea.
Gastrointestinal disorders
Uncommon: nausea, vomiting, diarrhoea.
Frequency not known: constipation, dry mouth
Skin and subcutaneous tissue disorders
Rare: Purpura, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, rashes.
Musculoskeletal system and connective tissue disorders Frequency not known: arthralgia Renal and urinary disorders
Frequency not known: reduced renal blood flow and GFR
Reproductive system and breast disorders
Frequency not known: sexual dysfunction
General disorders and administration site conditions
Common: Fatigue and/or lassitude (often transient); headache
Investigations:
Very rare: an increase in ANA (Antinuclear Antibodies) has been observed with many beta blockers, however the clinical relevance of this is not clear.
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 (see section 4.4). In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted (see section 4.9).
4.9 Overdose
Clinical features:
Cardiac - Bradycardia, hypotension, pulmonary oedema, syncope and cardiogenic shock may develop. Conduction abnormalities such as first or second degree AV block may occur. Rarely arrhythmias may occur. Development of cardiovascular complications is more likely if other cardioactive drugs, especially calcium channel blockers, digoxin cyclic antidepressants or neuroleptics have also been ingested. The elderly and those with underlying ischaemic heart disease are at risk of developing severe cardiovascular compromise.
CNS-Drowsiness, confusion, seizures, hallucinations, dilated pupils and in severe cases coma may occur. Neurological signs such as coma or absence of pupil reactivity are unreliable prognostic indicators during resuscitation.
Other features - bronchospasm, vomiting and occasionally CNS-mediated respiratory depression may occur. The concept of cardioselectivity is much less applicable in the overdose situation and systemic effects of beta-blockade include bronchospasm and cyanosis, particularly in those with pre-existing airways disease. Hypoglycaemia and hypocalcaemia are rare and occasionally generalised spasm may also be present.
Management
In cases of overdose or extreme falls in the heart rate or blood pressure, treatment with propranolol must be stopped. In addition to primary poison elimination measures, vital parameters must be monitored and corrected accordingly in intensive care.
This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal (50 g for adults, 1 g/kg for children) if an adult presents within 1 hour of ingestion of more than a therapeutic dose or a child for any amount. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.
Bradycardia may respond to large doses of atropine (3 mg intravenously for an adult and 0.04 mg/kg for a child).
For severe hypotension, heart failure or cardiogenic shock in adults a 5-10mg IV bolus of glucagon (50-150 micrograms/kg in a child) should be administered over 10 minutes to reduce the likelihood of vomiting, followed by an infusion of 1-5 mg/hour (50 micrograms/kg/hour), titrated to clinical response. If glucagon is not available or if there is severe bradycardia and hypotension, which is not improved by glucagon, isoprenaline at an infusion rate of 5-10 micrograms/minute (0.02 micrograms/kg/min in children increasing to a maximum of 0.5 micrograms/kg/min) and increased as necessary depending on clinical response.
In severe hypotension additional inotropic support may be necessary with a beta agonist such as dobutamine 2.5-40 micrograms/kg/min (adults and children).
Nebulised salbutamol 2.5-5 mg should be given for bronchospasm. Intravenous aminophylline may be of benefit in severe cases (5 mg/kg over 30 mins followed by an infusion of 0.5-1 mg/kg/hour). Do not give the initial loading dose of 5 mg/kg if the patient is taking oral theophylline or aminophylline.
Cardiac pacing may also be effective at increasing heart rate but does not always correct hypotension secondary to myocardial depression.
In cases of generalised spasm, a slow intravenous dose of diazepam may be used (0.1-0.3 mg/kg body weight).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: C07AA05 (propranolol)
Propranolol hydrochloride is a beta-adrenoceptor blocking agent.
Mode of Action
Propranolol is a competitive antagonist at both beta, and beta2-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1-3mg/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.
5.2 Pharmacokinetic properties
Propranolol is almost completely absorbed from the gastrointestinal tract, but it is subject to considerable first-pass metabolism. Peak plasma concentrations occur about two hours after a dose. It is metabolised in the liver, the metabolites being excreted in the urine together with only small amounts of unchanged Propranolol; at least one of its metabolites is considered to be biologically active.
The biological half-life of Propranolol is longer than would be anticipated from its plasma half-life of about 3 to 6 hours.
5.3 Preclinical safety data
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose B.P./Ph. Eur. Maize Starch B.P./Ph. Eur.
Povidone B.P./Ph. Eur.
(Industrial Methylated Spirits)
Colloidal Silicon Dioxide (Aerosil 200) U.S.P. Magnesium Stearate B.P./Ph. Eur. Methylcellulose (Methocel E5) B.P./Ph. Eur. Ethylcellulose (Ethocel 10 cps) B.P.)Ph. Eur. Diethyl Phthalate B.P./Ph. Eur.
(Methylene Chloride)
(Methanol)
Opaspray K-I-1340
6.2 Incompatibilities
There are no known major incompatibilities with propranolol tablets.
6.3 Shelf life
5 years (60 months).
6.4 Special precautions for storage
Store in a cool dry place below 25°C.
Protect from light and heat.
6.5 Nature and contents of container
Polypropylene securitainers with polypropylene tamper evident caps. Pack sizes : 28, 56, 100, 250, 500 and 1000 tablets.
6.6 Special precautions for disposal
Do not take this medicine if you have a history of wheezing or asthma.
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
3 & 4 Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
8
9
10
RE25 3ED UK
MARKETING AUTHORISATION NUMBER(S)
PL 20416/0383
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/07/2001
DATE OF REVISION OF THE TEXT
08/12/2014