Propranolol Tablets USP 60mg Taj Pharma

1.NAME OF THE MEDICINAL PRODUCT
a) Propranolol Tablets USP 10mg Taj Pharma
b) Propranolol Tablets USP 20mg Taj Pharma
c) Propranolol Tablets USP 40mg Taj Pharma
d) Propranolol Tablets USP 60mg Taj Pharma
e) Propranolol Tablets USP 80mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each tablet contains
Propranolol Hydrochloride USP 10mg
Excipients q.s.
Carmoisine (E122)

b) Each tablet contains
Propranolol Hydrochloride USP 20mg
Excipients q.s.
Carmoisine (E122)

c) Each tablet contains
Propranolol Hydrochloride USP 40mg
Excipients q.s.
Carmoisine (E122)

d) Each tablet contains
Propranolol Hydrochloride USP 60mg
Excipients q.s.
Carmoisine (E122)

e) Each tablet contains
Propranolol Hydrochloride USP 80mg
Excipients q.s.
Carmoisine (E122)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Pink film-coated tablets.
Pink, circular, biconvex film-coated tablets.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
1) Management of angina pectoris.
2) Control of hypertension.
3) Long-term prophylaxis against re-infarction after recovery from acute myocardial infarction.
4) Management of hypertrophic obstructive cardiomyopathy.
5) Management of essential tremor.
6) Relief of situational anxiety and generalised anxiety symptoms, particularly those of somatic type.
7) Control of most forms of cardiac arrhythmia.
8) Adjunctive management of thyrotoxicosis and thyrotoxic crisis.
9) Management of phaeochromocytoma peri-operatively (with an alpha-blocker).
10) Prophylaxis of migraine.
11) Prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices.

4.2 Posology and method of administration
Posology
Adults and children over 12 years:
Hypertension: Initially 80mg twice daily, which may be increased at weekly intervals according to response. The usual dose range is 160-320mg/daily. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.

Angina, migraine and essential tremor: Initially 40mg two or three times daily, increasing by the same amount at weekly intervals according to response. An adequate response in migraine and essential tremor is usually seen in the range 80-160mg daily, and in angina 120-240mg daily.

Situational and generalised anxiety: A dose of 40mg daily may provide short term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately to 40mg twice daily which, in individual cases, may be increased to 40mg three times daily. Treatment should be continued according to response. Patients should be reviewed after six to twelve months’ treatment.

Arrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: Most patients respond within the dosage range of 10-40mg three or four times daily.

Post myocardial infarction: Treatment should be initiated between days 5-21 after myocardial infarction, with an initial dose of 40mg four times daily for two or three 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. Dosing should begin with 40mg twice daily, increasing to 80mg twice daily depending on heart rate response. If necessary, the dose may be increased incrementally to a maximum of 160mg twice daily.

Phaeochromocytoma (used only in conjunction with an alpha-receptor blocking drug): Pre-operatively; 60mg daily for three days is recommended. Non-operable malignant cases, 30mg daily.

Elderly: Evidence concerning the relationship between blood level and age is conflicting. Propranolol tablets should be used to treat the elderly with caution. It is suggested that treatment should start with the lowest dose. The optimum dose should be individually determined according to clinical response.

Paediatric population
Children and Adolescents:
Arrhythmias, dysrhythmias, phaeochromocytoma, thyrotoxicosis: Dosage should be determined according to the cardiac status of the patient and the circumstances necessitating treatment. The doses given are intended only as a guide: 0.25-0.5mg/kg bodyweight 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 propranolol 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.

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 20mg 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
|For oral use.

The tablets should preferably be administered before meals.

4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Propranolol must not be used if there is a history of bronchial asthma, bronchospasm chronic obstructive airways disease. The product label states the following warning: “Do not take Propranolol 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.

Propranolol l as with other beta-blockers must not be used in patients with any of the following conditions: 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 or Prinzmetal’s angina.

Propranolol must not be used in patients prone to hypoglycaemia, i.e., patients after prolonged fasting or patients with restricted counter-regulatory reserves. Patients with restricted counter regulatory reserves may have reduced autonomic and hormonal responses to hypoglycaemia which includes glycogenolysis, gluconeogenesis and /or impaired modulation of insulin secretion. Patients at risk for an inadequate response to hypoglycaemia includes individuals with malnutrition, prolonged fasting, starvation, chronic liver disease, diabetes and concomitant use of drugs which block the full response to catecholamines.

4.4 Special Warnings and precautions for use
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.

Propranolol should not be used in combination with calcium channel blockers with negative inotropic effects (e.g. verapamil, diltiazem), as it 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-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

Concomitant therapy with dihydropyridine calcium channel blockers, e.g., nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

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.

Caution must be exercised if propranolol is given to patients with first degree heart block.

Propranolol may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Propranolol occasionally causes hypoglycaemia, even in non-diabetic patients, e.g. neonates, infants, children, 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. Caution must be exercised in the concurrent use of propranolol and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin (see section 4.3).

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.

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.

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.

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 necessary, when beta adrenoceptor blocking drugs are used in patients with a history of anaphylaxis.

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.

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.

Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days. Patients should be followed during withdrawal especially those with ischaemic heart disease.

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.

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.

Propranolol should 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.

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.

Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.

Carmoisine (E122)
Propranolol 10mg tablets contain carmoisine (E122) which may cause allergic reactions.

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.

Use of betablockers 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.

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 co-administered, 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 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. Simultaneous administration of rizatriptan and propranolol can cause an increased rizatriptan AUC and Cmax by approximately 70-80%. The increased rizatriptan exposure is presumed to be caused by inhibition of first-passage metabolism of rizatriptan through inhibition of monoamine oxidase-A. 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:
Concomitant use of prostaglandin synthetase inhibiting drugs eg, ibuprofen and indometacin, may decrease the hypotensive effects of propranolol.

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.

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: propafenone, thioridazine, dihydropyridine and calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine.

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.

4.6 Fertility, Pregnancy and lactation
Pregnancy
As with all other drugs, propranolol should not be given in pregnancy or lactation 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 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.

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.

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 (≥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

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)

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: 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

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

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)

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).

Reporting of suspected adverse reactions
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.

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).

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 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.

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
Pharmacotherapeutic group: beta blocking agents, non-selective
Propranolol hydrochloride is a beta-adrenoceptor blocking agent.

Mechanism 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.

Propranolol as with other beta-blockers, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.

Propranolol 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.

Propranolol is effective and well tolerated in most ethnic populations, although the response may be less in black patients.

5.2 Pharmacokinetic properties
Absorption
Propranolol is almost completely absorbed from the gastrointestinal tract, but it is subject to considerable first-pass metabolism.

Distribution
Peak plasma concentrations occur about 1 to 2 hours after dosing in fasting patients. 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%).

Biotransformation & Elimination
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 3-6 hours.

5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
The tablets contain: lactose, magnesium stearate, maize starch, stearic acid, hypromellose (E464).
The coating contains: carmoisine (E122), hypromellose (E464), polysorbate, titanium dioxide (E171), iron oxide red (E172).

6.2 Incompatibilities
None known.

6.3 Shelf life
3 years.

6.4 Special precautions for storage
Do not store above 25°C.

6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs and cartons:

a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M²PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.
Bulk pack: 50,000

6.6 Special precautions for disposal and other handling
Not applicable.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the patient

a) Propranolol Tablets USP 10mg Taj Pharma
b) Propranolol Tablets USP 20mg Taj Pharma
c) Propranolol Tablets USP 40mg Taj Pharma
d) Propranolol Tablets USP 60mg Taj Pharma
e) Propranolol Tablets USP 80mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4).

What is in this leaflet
1. What Propranolol Tablets is and what it is used for
2. What you need to know before you take Propranolol Tablets
3. How to take Propranolol Tablets
4. Possible side effects
5. How to store Propranolol Tablets
6. Contents of the pack and other information

1. WHAT PROPRANOLOL TABLETS IS AND WHAT IT IS USED FOR
Propranolol belongs to a group of medicines called beta-blockers. It is used to:
• treat high blood pressure, an enlarged heart muscle or tremors
• treat angina pectoris (pain in the chest caused by blockages in the arteries leading to the heart) or high blood pressure caused by a tumour near a kidney (phaeochromocytoma)
• help prevent additional heart attacks
• control irregular or fast heart beats
• control fast heart rate and other symptoms caused by an overactive thyroid gland
• to reduce migraine attacks
• calm people who are anxious or worried
• prevent stomach bleeding in patients with high blood pressure in their liver or swollen blood vessels in their gullet.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE PROPRANOLOL TABLETS
Do not take Propranolol tablets and tell your doctor if you:
• are allergic (hypersensitive) to Propranolol tablets or any of the other ingredients (see section 6)
• have untreated/uncontrolled heart failure or are in shock caused by heart problems
• suffer with heart conduction or rhythm problems
• have a slow heart rate
• have low blood pressure
• suffer from severe blood circulation problems (which may cause your fingers
and toes to tingle or turn pale or blue)
• suffer from diabetes mellitus (low blood sugar levels may be hidden by this medicine) and increased acidity of the blood (metabolic acidosis)
• are on a strict fasting diet
• suffer from a tight, painful feeling in the chest in periods of rest (Prinzmetal’s angina)
• suffer from asthma or any other breathing difficulties
• suffer from untreated phaeochromocytoma (high blood pressure due to a tumour near the kidney).

Warnings and precautions
Talk to your doctor or pharmacist before taking Propranolol tablets if you:
• have a history of allergic reactions
• suffer with muscle weakness (myasthenia gravis)
• have a heart weakness or first degree heart block
• have kidney or liver disease
• suffer from blood circulation problems (which may cause your fingers and toes to tingle or turn pale or blue).
• have symptoms of hyperthyroidism (increased appetite, weight loss, sweating)
• suffer with or have a history of psoriasis
• suffer from Raynaud’s disease (cold sensations in fingers and toes) or intermittent claudication (narrowing of arteries in the legs causing pain on walking)
• smoke
• are elderly

Other medicines and Propranolol tablets
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, especially:
• medicines to treat heart diseases such as verapamil, diltiazem, nifedipine, nisoldipine, nicardipine, isradipine, lacidipine and dihydropyridine
• medicines to treat irregular heartbeat (arrhythmia) such as disopyramide, quinidine, flecainide, amiodarone, propafenone
• ergotamine derivates or rizatriptan (to treat migraine)
• adrenaline (epinephrine) (used in anaphylactic shock)
• medicines to treat diabetes such as insulin
• lidocaine (to treat irregular heartbeat (arrhythmia) or as a local anaesthetic)
• Non-Steroidal Anti-Inflammatory Drugs (NSAID) such as indometacin
• medicines to treat heart conditions (digitalis glycosides) such as digoxin
• chlorpromazine and thioridazine (for mental illness)
• cimetidine (to treat stomach ulcers)
• other medicines to treat high blood pressure such as alpha blockers, clonidine, moxonidine, methyldopa or hydralazine
• levodopa (used in Parkinson’s disease)
• monoamine-oxidase inhibitors, imipramine or fluvoxamine (to treat depression)
• warfarin (to prevent clotting)
• rifampicin (to treat infection)
• barbiturates (to treat severe insomnia)
• theophylline (treating asthma and reversible airways obstruction)
• medicines to clear excess water from the body (diuretics)
• anaesthetics
• medicines to treat high blood pressure or difficulty passing urine such as prazosin
• smoking tobacco

Pregnancy and breast-feeding
Propranolol tablets are not recommended during pregnancy or breastfeeding. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
Propranolol tablets may cause visual disturbances, hallucinations, fatigue, mental confusion, dizziness or tiredness. Make sure you are not affected before you drive or operate machinery.

Propranolol tablets contain Lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product, as it contains lactose.

Propranolol tablets contain Carmoisine (E122)
Propranolol tablets contain carmoisine (E122) which may cause allergic reactions.

Alcohol intake
You are advised to avoid alcohol whilst taking this medicine.

Anaesthetics or tests
If you are going to have an anaesthetic or any blood or urine tests, please tell your doctor or dentist that you are taking Propranolol tablets.

If you see another doctor or go into hospital, let them know what medicines you are taking

3. HOW TO TAKE PROPRANOLOL TABLETS
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take with water before meals.
Do not stop taking this medicine unless your doctor tells you to stop.

Recommended doses:
Adults & children over 12 years:
• Angina, migraine or tremor – initially 40mg two or three times a day, then 120- 240mg a day for angina or 80-160mg a day for migraine or tremor.
• High blood pressure – initially 80mg twice a day, then 160-320mg a day.
• Irregular/fast heart beats, over active thyroid gland or enlarged heart muscle – 10- 40mg three or four times a day.
• Heart attack (start treatment 5-21 days after attack) – 40mg four times a day for 2-3 days, then 80mg twice a day.
• Phaeochromocytoma – before an operation – 60mg a day for 3 days. – treatment dose – 30mg a day.
• Anxiety – 40mg before anxious situations. For long-term anxiety 40mg two or three times a day, treatment is reviewed after 6-12 months.
• High blood pressure within veins – initially 40mg twice a day, increasing to 80mg twice a day depending on response. Maximum dose 160mg twice a day.

Children and Adolescents:
• Irregular heartbeats, phaeochromocytoma, thyrotoxicosis, Fallot’s tetralogy – Doses are decided using body weight.
• Migraine – 20mg two to three time daily.

Elderly: your dose may be reduced.

Kidney impairment Your doctor may prescribe you a different dose.

Liver impairment Your doctor may prescribe you a different dose.

If you take more Propranolol tablets than you should
If you have accidentally taken more than the prescribed dose, contact your nearest casualty department or tell your doctor or pharmacist at once. Overdose causes difficulty breathing, low blood pressure, drowsiness, fits, dilated pupils, an excessively slowed heart beat with symptoms such as dizziness, sickness, confusion, hallucinations, body spasms, breathlessness on exertion, fainting or coma. Overdose could result in heart attack.

If you forget to take Propranolol tablets
If you forget to take a dose, take it as soon as you remember, unless it is nearly time for your next dose. Then go on as before. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Propranolol tablets
If you stop taking propranolol tablets suddenly you may experience unpleasant side effects including sweating, shaking, worsening of angina, irregular or fast heartbeat, heart attack or death. Withdrawal should be gradual over 10 to 14 days.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can have side effects, although not everybody gets them.

Stop treatment and contact a doctor at once if you have the following symptoms of an:
• intolerance to Propranolol tablets such as slow heart rate and low blood pressure causing dizziness, light-headedness, fainting or blurred vision
• allergic reaction such as itching, difficulty breathing or swelling of the face, lips, throat or tongue

Tell your doctor if you notice any of the following side effects or notice any other effects not listed:

Common (may affect up to 1 in 10 people):
• tiredness and/or weakness (these symptoms usually disappear), cold extremities, difficulty in sleeping
• slow or irregular heartbeat, Raynaud’s syndrome
• nightmares

Uncommon (may affect up to1 in 100 people):
• feeling or being sick, or diarrhoea

Rare (may affect up to1 in 1,000 people):
• your medicine may alter the number and types of your blood cells. If you notice increased bruising, nosebleeds, sore throats or infections, you should tell your doctor who may want to give you a blood test
• worsening of heart failure, heart block, low blood pressure/fainting on standing, dizziness, worsening of Intermittent claudication (pain and/or cramp in the leg caused by reduced blood flow)
• skin rash, worsening of psoriasis, hair loss, dry flaky skin, red/itchy skin, disorder characterised by blood spots, bruising and discolouring to skin
• hallucinations, mood changes, pins and needles, psychoses, memory loss, confusion
• patients with asthma or a history of breathing problems may experience difficulty in breathing
• dry eyes, visual disturbances

Very rare (may affect up to 1 in 10,000 people)
• development or worsening of myasthenia gravis (disorder characterised by muscle weakness, difficulty chewing or swallowing and slurred speech)

Not known (frequency cannot be estimated from the available data):
• signs of hyperthyroidism may be hidden
• changes in blood fats, changes in kidney function
• changes in blood sugar levels
• fits (seizures) linked to low blood sugar levels
• worsening of angina, headache, depression
• constipation, dry mouth, conjunctivitis (inflammation of the front surface of the eye causing red, sore, itching or weeping eyes)
• changes in sex drive or potency
• joint pain

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE PROPRANOLOL TABLETS
Keep Propranolol tablets out of the sight and reach of children.
Do not store the tablets above 25°C.
Do not take the tablets after the expiry date which is stated on the carton. The expiry date is also stated on the back of the strip after ‘Exp’. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. CONTENTS OF THE PACK AND FURTHER INFORMATION

What Propranolol Tablets contain
The active substance (the ingredient that makes the tablets work) is propranolol hydrochloride.
a) Each tablet contains
Propranolol Hydrochloride USP 10mg
Carmoisine (E122)

b) Each tablet contains
Propranolol Hydrochloride USP 20mg
Carmoisine (E122)

c) Each tablet contains
Propranolol Hydrochloride USP 40mg
Carmoisine (E122)

d) Each tablet contains
Propranolol Hydrochloride USP 60mg
Carmoisine (E122)

e) Each tablet contains
Propranolol Hydrochloride USP 80mg
Carmoisine (E122)

the other ingredients are lactose, magnesium stearate, maize starch, stearic acid, hypromellose (E464).
• the coating contains polysorbate, carmoisine (E122), titanium dioxide (E171), iron oxide red (E172), hypromellose (E464).

What Propranolol Tablets look like and contents of the pack
The tablets are pink, circular, film-coated tablets. Pack sizes are 28 and 56 tablets.
Not all pack sizes may be available.