Propranolol Tablets Bp 80mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Propranolol 80 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 80 mg Propranolol Hydrochloride.
Excipients with known effect: Also contains Lactose 93mg For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet
Pink biconvex film coated tablets embossed with ‘3’ on one side and break line on the other side.
The score line is not intended for breaking the tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
• Angina pectoris.
• Hypertension.
• Long-term prophylaxis against myocardial reinfarction after recovery from acute myocardial infarction Hypertrophic obstructive cardiomyopathy.
• Essential tremor.
• Supraventricular cardiac arrhythmia.
• Ventricular cardiac arrythmias.
• Hyperthyroidism and thyrotoxicosis Phaeochromocytoma (with an alpha-blocker).
• Migraine.
• Prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices.
4.2 Posology and method of administration
Posology
Adults:
Angina pectoris:
The starting dose is 40 mg two to three times daily, increasing by the same amount at weekly intervals according to the response. The dose may be increased to120 - 240 mg daily.
Migraine:
The starting dose is 40 mg two to three times daily. The dose may be increased to 80mg -160 mg daily.
Essential tremor:
The starting dose is 40 mg two to three times daily. For these indications the dosage and the dose intervals should be adapted to individual patient needs.
Hypertension: Initially 40 mg two or three times daily, which may be increased by 80 mg per day at weekly intervals according to response. The usual dose range is 160-320 mg daily. With concurrent diuretic and/or peripheral vasodilators a further reduction of blood pressure is obtained.
Arrhythmias The starting dose is 10 mg to -40 mg two or three times a day.
Hypertrophic obstructive cardiomyopathy:
Most patients respond within the dosage range of 10-40mg three or four times daily.
Hyperthyroidism: The dose is adjusted according to clinical response.
Post myocardial infarction: Treatment should be initiated when myocardial infarction has been stabilized with an initial dose of 40 mg 2-3 times daily for two or three days. In order to improve compliance, the total daily dosage may thereafter be given as 80 mg twice a day.
Thyrotoxicosis:
Most patients respond within the dosage range of 10-40 mg three or four times daily.
Hyperthyroidism: The dose is adjusted according to clinical response.
Phaeochromocytoma (used only in conjunction with an alpha-receptor blocking drug): Pre-operatively; 60 mg daily for three days is recommended. In-operable malignant cases, 30 mg daily.
Portal Hypertension: Dosage should be titrated to achieve approximately 25% reduction in heart rate at rest. Dosing 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.
Children and Adolescent:
Arrhythmias: Dosage should be determined according to the cardiac status of the patient and the circumstances necessitating treatment. The dose should be adjusted individually and the following is a guide: Children and adolescents: 0.25-0.5 mg/kg 3-4 times daily, adjusted according to clinical response.
Elderly:
Evidence concerning the relationship between blood level and age is conflicting. The optimum dose should be individually determined according to clinical response.
Hepatic impairment:
The bioavailability of propranolol may be increased in patients with hepatic impairment and dose adjustments may be required. In patients with severe liver disease (e.g. cirrhosis) a low initial dose is recommended (not exceeding 20 mg three times a day) with close monitoring of the response to treatment(such as the effect on heart rate).
Renal impairment:
Concentrations of propranolol may increase in patients with significant renal impairment and haemodialysis. Caution should be exercised when starting treatment and selecting the initial dose.
Method of administration:
The tablets should preferably be administered before meals.
For oral administration.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Cardiac decompensation which is not adequately treated.
• Sick sinus syndrome/SA-block.
• History of bronchospasm or bronchial asthma, chronic obstructive pulmonary disease.
• Metabolic acidosis.
• Second and third-degree heart block.
• Prolonged fasting (eg hypoglycaemia).
• Cardiogenic shock
• Untreated phaeochromocytoma.
• Severe bradycardia
• Severe hypotension
• Severe peripheral arterial disturbances
• Prinzmetal's angina
This warning will appear on the label: DO NOT TAKE THIS MEDICINE IF YOU HAVE A HISTORY OF WHEEZING OR ASTHMA.
4.4 Special warnings and precautions for use
In patients with chronic obstructive pulmonary disease, non-selective beta blockers such as propranolol may aggravate the obstructive condition. Therefore propranolol should not be used in this condition. (see section 4.3).
Severe hepatic or renal impairment. 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.
AV block grade I: Caution must be exercised if propranolol is given to patients with first degree heart block.
Decompensated liver cirrhosis: Propranolol should be used with caution in patients with decompensated cirrhosis.
Propranolol may mask signs of thyrotoxicosis or hypoglycaemia (especially tachycardia). Care must be taken in diabetic patients with concomitant hypoglycemic therapy. Propranolol can cause prolonged hypoglycemic episodes in these patients. Propranolol may occasionally cause hypoglycemia even in non-diabetics, such as neonates, infants, children, elderly, patients on hemodialysis, patients with chronic liver disease, patients taking an overdose and prolonged fasting. 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.
As with other beta-adrenoceptor blocking agents, 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.
Propranolol may enhance an anaphylactic reaction. Beta adrenoceptor 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.
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.
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.
Surgery: When it has been decided to interrupt a beta-blockade in preparation for surgery, therapy should be discontinued for at least 48 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, however the risk of hypotension may be increased as well. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. The patient may be protected against vagal reactions by intravenous administration of atropine.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Combination not recommended
Beta-agonist bronchodilators:
Non-cardioselective beta-blockers oppose the bronchodilator effects of beta-agonist bronchodilators, propranolol is contraindicated in patients with asthma (see section 4.3).
Calcium channel blockers (Verapamil, diltiazem or bepridil):
Calcium channel blockers and beta-blockers have additive effects on AV conduction and sinus node function and can cause bradycardia and hypotension. The combination with propranolol should be avoided, especially in patients with cardiac decompensation (see section 4.4).
Fingolimod:
Potentiation of bradycardia effects with possible fatal outcomes. Treatment with Fingolimod should not be initiated in patients receiving beta blockers. In case of combination, appropriate monitoring for treatment initiation, at least overnight monitoring is recommended.
Barbiturates:
The plasma levels and the effects of beta-blockers are reduced by the barbiturates. Barbiturates are potent liver enzyme inducers which may increase the metabolism of propranolol.
Propafenone:
Plasma propranolol levels can be raised up to 100% by propafenone. This probably was because propranolol is partially metabolized by the same enzyme like propafenone (CYP2D6). This combination is also not advisable because propafenone has negative inotropic effects.
MAO inhibitors:
Concomitant use of MAO inhibitors (except MAO-B inhibitors) with antihypertensive agents may diminish the antihypertensive effect and lead to hypertensive reactions.
Combination to be used with caution, dose adjustment may be required Amiodarone:
A few case reports suggest that patients treated with amiodarone can have severe sinus bradycardia when treated concomitantly with propranolol. Amiodarone has an extremely long half-life (about 50 days), which means that interactions may occur long after discontinuation of therapy.
Class I antiarrhythmic drugs (disopyramide, quinidine):
Class I antiarrhythmic drugs and beta-blockers have additive negative inotropic effects which may result in hypotension and severe hemodynamic side effects in patients with impaired left ventricular function. Quinidine appears to increase propranolol plasma levels by inhibiting the CYP2D6, thereby reducing its clearance. Therefore dose of propranolol should be reduced at the initiation of treatment with quinidine.
Non-steroidal anti-inflammatory / anti-rheumatic drugs (NSAIDs):
Anti-inflammatory drugs of NSAID-type counter the antihypertensive effect of beta-blockers. It has been studied mainly in indomethacin. In a study on diclofenac no such interaction could be detected. Data for COX-2 inhibitors are missing.
Cimetidine:
Cimetidine increases levels of propranolol in plasma, probably by inhibiting its first pass metabolism. There may be a risk of eg bradycardia with oral dosing.
Anaesthetics:
Concomitant use of beta-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension (see section 4.4). As a general rule, avoid sudden withdrawal of beta-blocker treatment. The anaesthesiologist should be informed when the patient is receiving beta-adrenergic antagonists.
Epinephrine (adrenaline):
A number of reports are available for severe hypertension and bradycardia in patients treated with propranolol and epinephrine. These clinical observations have been confirmed by studies in healthy volunteers. It has also been suggested that the intravascular administration of epinephrine may trigger these reactions.
Fluvoxamine:
Fluvoxamine inhibits oxidative metabolism and increases plasma concentrations of propranolol. This may result in severe bradycardia.
Centrally-acting antihypertensives (clonidine, moxonidine, methyldopa):
Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of “rebound hypertension”
Rifampicin:
The metabolism of propranolol may be increased by potent liver enzyme inducer rifampicin.
Alpha blockers:
Concomitant use with alpha blockers increases the risk of hypotension, especially orthostatic hypotension, and tachycardia and palpitations
Dihydropyridine calcium channel blockers:
Concomitant use may increase the risk of hypotension.
Chlorpromazine:
The concurrent use of chlorpromazine with propranolol can result in a marked rise in plasma levels of both drugs, and thereby enhance its effects on heart rate and blood pressure.
Lidocaine:
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.
Antimigraine drugs:
During concomitant treatment with propranolol it inhibited the first-pass metabolism of rizatriptan whose AUC increases by 70-80%. A dose of 5 mg of rizatriptan is recommended for combination therapy. Ergotamine with propranolol has resulted in reports of vasospastic reactions in some patients.
Theophylline:
Propranolol reduces the metabolic clearance of theophylline by about 30% at a dosage of 120 mg / day and 50% at doses of 720 mg / day.
Insulin and oral antidiabetic drugs:
Concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia). Propranolol may prolong the hypoglycaemic response to insulin.
Tobacco:
Tobacco smoking can reduce the beneficial effects of the beta-blockers on heart rate and blood pressure.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are insufficient data from the use of propranolol in pregnant women to judge any possible harmfulness. Up to now there is no evidence for an increased risk of birth defects in humans. Animal studies do not indicate harmful effects on reproduction. Based on the pharmacodynamic mechanism of action, possible induction of side effects in the foetus and neonates should be taken into consideration when used late in pregnancy (in particular bradycardia, hypoglycemia and hypotension). In general, beta-blockers reduce placental blood flow. Propranolol tablets may be taken during pregnancy only if strongly indicated.
Breast-feeding
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.
Fertility
No relevant data on effect of fertility in humans is available.
4.7 Effects on ability to drive and use machines
Regular medical follow up is required during treatment with this medicinal product. Because reactions differ between individuals the ability to react can be affected to such an extent that the ability to drive, operate machines or work without a secure footing is impaired. This effect is greater at the start of treatment, when the dose is increased, following a treatment switch and in conjunction with alcohol.
4.8 Undesirable effects Summary of the safety profile
Side effects are mostly related to the pharmacological effect. Most common are fatigue, including muscle weakness reported in between 3-5%.
Adverse reactions related to propranolol are listed below by system organ class and frequency. Frequencies are defined as:
Very common (>1/10); common (>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
Immune system disorders
Rare: angioedema.
Endocrine disorders
Frequency not known: masking signs of thyrotoxicosis.
Metabolic and nutritional disorders
Frequency not known: 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. Changes in lipid metabolism (changes in blood concentrations of triglycerides and cholesterol). Severe hypoglycemia may rarely lead to seizures or coma.
Psychiatric disorders
Common: Sleep disturbances, nightmares.
Rare: Hallucinations, psychoses, mood changes Frequency not known: depression Nervous system disorders
Rare: 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: visual disturbances, dry eyes 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 syndrome Rare: exacerbation of intermittent claudication,
Respiratory thoracic and mediastinal disorders
Common: breathlessness
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: diarrhoea, nausea, vomiting
Frequency not known: constipation, dry mouth
Skin and subcutaneous tissue disorders
Rare: alopecia, purpura, psoriasiform skin reactions, exacerbation of psoriasis, rash
Very rare: isolated cases of hyperhidrosis has been reported.
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: impotence General disorders and administration site conditions Common: fatigue and/or lassitude (often transient)
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 wellbeing 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).
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose Toxicity:
Individual response varies greatly, death in adults has followed ingestion of about 2 g, and ingestion of more than 40 mg may cause serious problems in children.
Symptoms:
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 cardio selectivity 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. . In case of cardiac arrest, the resuscitation of several hours may be indicated.
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. Atropin should be administrated before gastric lavage, when required as there is a risk of vagal stimulation. 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, the beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, dopamine or noradrenalin.
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
Pharmacotherapeutic group: Beta blocking agents, non-selective (beta blocker)
ATC code: C07AA05
The substance has no P-1 receptor selectivity (cardio selectivity) and has no intrinsic sympathomimetic activity (ISA). Propranolol is a strongly lipophilic substance and has a membrane stabilising effect.
These properties are important in connection with the occurrence of undesirable effects and/or overdose.
5.2 Pharmacokinetic properties
Propranolol is completely absorbed after oral administration. Peak plasma concentration is reached 1 to 2 hours after oral administration in fasting patients. Up to approx. 90% of the oral dose is eliminated via the liver. The first pass effect results in low and variable bioavailability and there is wide inter-individual variation in plasma levels. The elimination half-life is 3 to 6 hours. Propranolol belongs to the lipophilic P-blockers. It is rapidly distributed throughout the body, with high concentrations in the lungs, liver, kidneys, brain and heart. The active 4-OH metabolite of propranolol is formed in the liver. Propranolol is 80-95% bound to serum proteins, especially the variable protein component: a1-acid glycoproteins.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, local tolerance, genotoxicity, carcinogenic potential and toxicity to reproduction.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Maize starch Povidone
Sodium starch glycolate Magnesium stearate Hydroxypropylmethyl cellulose Polyethylene glycol 400 Titanium dioxide (E171)
Opaspray M-1-1300B Pink
Incompatibilities
6.2
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister pack comprising of PVC/PVDC white opaque 250/40 gsm; Aluminium Foil 20 microns.
Blister pack comprising of PVC/PVDC white opaque 250/90 gsm; Aluminium Foil 20 microns.
Pack size of 28, 56 Tablets.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Unit 3 Canalside Northbridge road Berkhamsted HP4 1EG UK
MARKETING AUTHORISATION NUMBER(S)
PL 17907/0328
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
3rd April 2002
10
DATE OF REVISION OF THE TEXT
03/11/2016