1 NAME OF THE MEDICINAL PRODUCT

Angivert 75mg Dispersible Tablets Dispersible Aspirin Tablets BP 75mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains aspirin BP 75mg.

3    PHARMACEUTICAL FORM

Dispersible tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery.

4.2 Posology and method of administration

The advice of a doctor should be sought before commencing therapy for the first time.

Adults, the elderly and children over 16:

The usual dosage for long term use in the management of cardiovascular or cerebrovascular disease is 75-150mg once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 300mg a day may be used on the advice of a doctor.

Children under 16:

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki’s disease). (See ‘Special Warnings and Special Precautions for Use’).

Method of administration:

Angivert Dispersible Tablets/Dispersible Aspirin Tablets should be dissolved in a glass of water and taken orally.

4.3 Contraindications

Due to the increased risk of Reye’s syndrome, aspirin is not recommended in children under 16 years of age unless specifically indicated (e.g. for Kawasaki's disease).

Other contraindications include active peptic ulceration or a history of peptic ulceration, gout, breast feeding, haemophilia, asthma, urticaria, rhinitis, concurrent anticoagulant therapy, hypersensitivity to acetylsalicylic acid and other NSAIDs, haemorrhagic disease, and severe renal or hepatic impairment.

4.4 Special warnings and precautions for use

Administer with caution in the presence of allergic disease, renal or hepatic impairment, or dehydration. Acetylsalicylic acid may trigger haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

There is a possible association between aspirin and Reye’s syndrome when given to children. Reye’s syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki’s disease).

Elderly patients may be more susceptible to the toxic effects of salicylates.

Before commencing long-term therapy for the management of cardiovascular or cerebrovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.

Aspirin may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Continuous prolonged use of aspirin should be avoided in the elderly because of the risk of gastrointestinal bleeding.

Aspirin may interfere with insulin and glucagon in diabetes.

Aspirin prolongs bleeding time, mainly by inhibiting platelet aggregation and therefore it should be discontinued several days before scheduled surgical procedures. Haematological & haemorrhagic effects can occur, and may be severe. Patients should report any unusual bleeding symptoms to their physician.

Salicylates should not be used in patients with a history of coagulation abnormalities as they may also induce gastro-intestinal haemorrhage, occasionally major. (see section 4.3)

Aspirin should not be taken by patients with a stomach ulcer or a history of stomach ulcers. (see section 4.3)

Patients with hypertension should be carefully monitored.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants: Aspirin may potentiate the effect of heparin and increases the risk of bleeding with oral anticoagulants, antiplatelet agents and fibrinolytics. Concomitant use is not recommended (see Section 4.3).

Other non-steroidal anti-inflammatory drugs (NSAIDs): Concurrent administration can increase side effects. Use of two or more NSAIDs increases risk of gastrointestinal haemorrhage. Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Corticosteroids: The risk of gastrointestinal bleeding and ulceration is increased. Corticosteroids reduce the plasma salicylate concentration and salicylate toxicity may occur following withdrawal of corticosteroids.

Carbonic anhydrase inhibitors: Reduced excretion of acetazolamide; salicylate intoxication has occurred in patients on high dose salicylate regimes and carbonic anhydrase inhibitors. Concurrent administration of carbonic anhydrase inhibitors such as acetazolamide and salicylates may result in severe acidosis and increased central nervous system toxicity.

Antacids and adsorbents: The excretion of aspirin is increased in alkaline urine; kaolin possibly reduces absorption. Patients should be advised against ingesting antacids simultaneously to avoid premature drug release.

Mifepristone: The manufacturer of mifepristone recommends that aspirin should be avoided until eight to twelve days after mifepristone has been discontinued.

Antimetabolites: The activity of methotrexate may be markedly enhanced and its toxicity increased by concomitant use of aspirin.

Antibacterials: The toxicity of sulfonamides may be increased.

Alcohol: Some of the effects of aspirin on the gastrointestinal tract are enhanced by alcohol.

Antiemetics: Metoclopramide enhances the effects of aspirin by increasing the rate of absorption.

ACE inhibitors: Aspirin may reduce the antihypertensive effect of ACE inhibitors. Anti-epileptics: May enhance the effects of phenytoin and sodium valproate.

Diuretics: Antagonism of the diuretic effect of spironolactone.

Hypoglycaemic agents: Aspirin may enhance the effects of insulin and oral hypoglycaemic agents.

Leukotriene antagonists: The plasma concentration of zafirlukst is increased.

Uricosurics: Effect of probenecid and sulfinpyrazone may be reduced.

Thyroid function tests: Aspirin may interfere with thyroid function tests.

4.6 Fertility, Pregnancy and lactation

Acetylsalicylic acid should not be taken during pregnancy, unless directed by a doctor. Do not administer at term or during lactation.

The use of analgesic doses of aspirin during pregnancy, particularly during the third trimester, should be avoided. The drug may affect maternal and newborn haemostatic mechanisms, leading to an increased risk of haemorrhage. Aspirin may also delay the onset and increase the duration of labour. With high doses, there may be premature closure of the ductus arteriosus, leading possibly to persistent pulmonary hypertension. The use of low doses of aspirin, for the secondary prevention of myocardial infarction and stroke are probably not harmful.

Aspirin is secreted into breast milk in low concentration and should therefore be avoided during lactation because of the possible risk of Reye's Syndrome and the fact that high doses could potentially impair platelet function.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Side effects are generally mild and infrequent:

Blood and the lymphatic system disorders: Aspirin prolongs bleeding time, decreases platelet adhesiveness and, in large doses, may cause hypoprothrombinaemia. Thrombocytopenia may also occur. Bleeding disorders such as epistaxis, haematuria, purpura, ecchymoses, haemoptysis, gastrointestinal bleeding, haematoma and cerebral haemorrhage have occasionally been reported. Fatalities have occurred. Haemolytic anaemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Immune system disorder: Hypersensitivity reactions include skin rashes, urticaria, angioedema, asthma, severe bronchospasm, rhinitis, angioneurotic oedema and rarely, anaphylaxis.

Ear & Labyrinth disorder: Tinnitus.

Gastrointestinal disorders: Gastrointestinal irritation is common in patients taking aspirin preparations, and nausea, vomiting dyspepsia, gastritis, gastrointestinal erosions and ulceration have been reported. Anaemia may occur following chronic gastrointestinal blood loss or acute haemorrhage.

Skin and subcutaneous tissue disorders: Skin reactions may occur in susceptible patients. Renal and Urinary disorders: urate kidney stones.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features: Salicylate poisoning produces dizziness, tinnitus, dehydration, vertigo, deafness, warm extremities with bounding pulses, increased respiratory rate, sweating, nausea and vomiting, confusion and hyperventilation. Gastric lavage, forced alkaline diuresis and supportive therapy, restoration of acid-base balance may be necessary.

In adults and children over the age of 4 years, a mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is common. A dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is usual in children aged 4 years or less. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features of salicylate poisoning include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation of 1.26% sodium bicarbonate. The urine pH should be monitored.

Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700 mg/L (5.1mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5.1 Pharmacodynamic properties

B01A C (blood and blood forming organs — antithrombotic agents)

Aspirin has analgesic, anti-inflammatory and anti-pyretic activity which is considered to be due to inhibition of the synthesis of prostaglandins. It also has an antithrombotic action, mediated through inhibition of platelet activation, which has been shown to be useful in secondary prophylaxis following myocardial infarction and in patients with unstable angina or ischaemic stroke including cerebral transient attacks.

In the body it is rapidly converted to the salicylate form which has similar activity and works via the inhibition of the enzyme cyclo-oxygenase inhibiting prostaglandin synthesis. Aspirin also inhibits platelet aggregation by irreversible acetylation of platelet cyclo-oxygenase.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic properties

Absorption: Aspirin is rapidly absorbed after oral administration, with some hydrolysis to salicylate before absorption. Absorption is delayed by the presence of food and is impaired in patients suffering migraine attacks. Absorption is more rapid in patients with achlorhydria and also following administration of polysorbates and antacids.

Absorption of non-ionised aspirin occurs in the stomach and intestine. Some aspirin is hydrolysed to salicylate in the gut wall. After absorption aspirin is rapidly converted to salicylate but during the first 20 minutes following oral administration, aspirin is the predominant form of the drug in the plasma. Aspirin is bound to plasma proteins and is widely distributed. Plasma aspirin concentrations decline rapidly (half life 15-20 minutes) as plasma salicylate concentrations increase.

Distribution: Aspirin is found in the saliva, milk, plasma and synovial fluid at concentrations less than blood and crosses the placenta.

Salicylate -extensive protein binding.

Aspirin -protein binding to a small extent.

Metabolism: In the blood, rapid hydrolysis to salicylic acid; glucuronic acid/ glycine conjugation to form glucuronides and salicyluronic acid; oxidation of a small proportion.

Elimination:    Salicylate is mainly eliminated by hepatic metabolism the metabolites

including salicylic acid, salicyl phenolic glucuronide, salicylic acyl glucuronide, gentisic acid and gentisuric acid. As a result of zero order kinetics, plasma steady state salicylate concentrations increase disproportionately with dose.

Salicylate is excreted in the urine mainly as salicyluronic acid. Salicylate reabsorbed by renal tubules in acid urine, and alkaline diuresis will increase the rate of excretion; 85% of dose excreted as free salicylate.

5.3    Preclinical safety data

There are no preclinical 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

Maize starch, sodium saccharin, lactose granules, anhydrous citric acid, calcium carbonate, talc and sodium lauryl sulphate.

Incompatibilities

Not known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Protect from heat, light and moisture.

6.5 Nature and contents of container

Blister pack: pack size: 24.

Snapsafe: pack size: 25, 50 and 100.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate, Riverside Way,

Dartford

DA15BS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0025

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30 July 1992

10    DATE OF REVISION OF THE TEXT

13/08/2014