4.1. Therapeutic indications

- Secondary prevention of myocardial infarction.

- Prevention of cardiovascular morbidity in patients suffering from stable angina pectoris.

- History of unstable angina pectoris, except during the acute phase.

- Prevention of graft occlusion after Coronary Artery Bypass Grafting (CABG).

- Coronary angioplasty, except during the acute phase.

- Secondary prevention of transient ischaemic attacks (TIA) and ischaemic cerebrovascular accidents (CVA), provided intracerebral haemorrhages have been ruled out.

- Acute myocardial infarction.

4.2. Posology and method of administration

Posology

Adults

Secondary prevention of myocardial infarction:

The recommended dose is 75-160 mg once daily.

Prevention of cardiovascular morbidity in patients suffering from stable angina pectoris:

The recommended dose is 75-160 mg once daily.

History of unstable angina pectoris, except during the acute phase:

The recommended dose is 75-160 mg once daily.

Prevention of graft occlusion after Coronary Artery Bypass Grafting (CABG):

The recommended dose is 75-160 mg once daily.

Coronary angioplasty, except during the acute phase:

The recommended dose is 75-160 mg once daily.

Secondary prevention of transient ischaemic attacks (TIA) and ischaemic cerebrovascular accidents (CVA), provided intracerebral haemorrhages have been ruled out:

The recommended dose is 75-300 mg once daily.

Acute myocardial infarction:

The recommended loading dose is 150-300 mg followed by a lower dose (75-160 mg) daily thereafter.

Aspirin should not be used at higher doses unless advised by a doctor, and the dose should not exceed 300 mg a day.

Elderly patients

In general, acetylsalicylic acids should be used with caution in elderly patients who are more prone to adverse events. The usual adult dose is recommended in the absence of severe renal or hepatic insufficiency (see sections 4.3 and 4.4). Treatment should be reviewed at regular intervals.

Paediatric population

Acetylsalicylic acid should not be administered to children and adolescents younger than 16 years, except on medical advice where the benefit outweighs the risk (see section 4.4).

Method of administration

For oral use.

The tablets should be swallowed with sufficient fluid (1/2 glass of water).

Duration of administration:

Long-term treatment with the lowest possible dose.

4.3. Contraindications

- Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to salicylates/aspirin or other substances with a similar mechanism of action, especially non-steroidal anti-inflammatory drugs (NSAIDs) A history of asthma caused by salicylates or substances with a similar mechanism of action, especially NSAIDs;

- Acute gastrointestinal ulcers;

- A history of gastrointestinal bleeding or perforation (gastric or intestinal failure) caused by previous NSAID therapy;

- Active or a history of recurrent gastric and duodenal ulcer/haemorrhage with episodes of proven ulceration or bleeding, or other kinds of bleeding such as cerebrovascular haemorrhages;

- Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia;

- Severe hepatic impairment;

- Severe renal impairment;

- Severe cardiac insufficiency;

- Doses >100 mg/day during the third trimester of pregnancy (see section 4.6);

- Methotrexate used at doses >15 mg/week (see section 4.5).

4.4. Special warnings and precautions for use

Aspirin is not suitable for use as an anti-inflammatory, analgesic or antipyretic.

Recommended for use in adults and adolescents from 16 years of age. This medicinal product is not recommended for use in adolescents/children under 16 years unless the expected benefits outweigh the risks. Acetylsalicylic acid may be a contributory factor in the causation of Reye's Syndrome in some children.

There is an increased risk of haemorrhage and prolongation of bleeding time particularly during or after surgery (even in cases of minor procedures, e.g. tooth extraction). Use with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary.

Aspirin is not recommended during menorrhagia where it may increase menstrual bleeding.

Aspirin is to be used with caution in cases of uncontrolled hypertension and when patients have a past history of gastric or duodenal ulcer or haemorrhagic episodes or are undergoing therapy with anticoagulants.

Patients should report any unusual bleeding symptoms to their physician. If gastrointestinal bleeding or ulceration occurs the treatment should be withdrawn.

Acetylsalicylic acid should be used with caution in patients with moderately impaired renal or hepatic function (contraindicated if severe), or in patients who are dehydrated since the use of NSAIDs may result in deterioration of renal function. Liver function tests should be performed regularly in patients presenting slight or moderate hepatic insufficiency.

Acetylsalicylic acid may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g. with skin reactions, itching or urticaria). Aspirin should not be used in patients with a history of asthma caused by salicylates or NSAIDs (see section 4.3).

Serious skin reactions, including Stevens-Johnson syndrome, have rarely been reported in association with the use of acetylsalicylic acid (see section 4.8). The treatment with Aspirin should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Elderly patients are particularly susceptible to the adverse effects of NSAIDs and acetylsalicylic acid especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). Where prolonged therapy is required, these patients should be reviewed regularly.

Concomitant treatment with Aspirin and drugs that alter haemostasis (i.e. anticoagulants, thrombolytic agents, antiplatelet agents, anti-inflammatory drugs and selective serotonin reuptake inhibitors) is not recommended, unless strictly indicated, because they may enhance the risk of haemorrhage (see section 4.5). If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration, such as oral corticosteroids, selective serotonin-reuptake inhibitors and deferasirox (see section 4.5).

Acetylsalicylic acid in low doses reduces uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks (see section 4.5 and 4.8).

The risk of hypoglycaemic effect with sulfonylureas and insulins may be potentiated with Aspirin taken at overdosage (see section 4.5).

Aspirin should be used with caution in patients with Glucose-6-phosphate dehydrogenase deficiency.

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Contraindicated combinations

Methotrexate (used at doses >15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, enhance haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15 mg/week) with Aspirin is contraindicated (see section 4.3).

Not recommended combinations

Uricosuric agents, e.g. probenecid, sulfinpyrazone

Salicylates reverse the effect of probenecid and sulfinpyrazone. The combination should be avoided.

Combinations requiring precautions for use or to be taken into account

Anticoagulants and thrombolytics

Acetylsalicylic acid may increase the effects of thrombolytic agents. Increased risk of bleeding due to inhibited thrombocyte function, injury of the duodenal mucosa and displacement of oral anticoagulants from their plasma protein binding sites. Patients that are treated concomitantly with acetylsalicylic acid and other antithrombotic agents should be carefully monitored for signs of bleeding (see section 4.4).

Particularly, treatment with acetylsalicylic acid should not be initiated within the first 24 hours after treatment with alteplase in acute stroke patients.

Anti-platelet agents (e.g clopidogrel,ticlopidine, cilostazol and dipyridamole) and selective serotonin reuptake inhibitors (SSRIs; such as sertraline or paroxetine)

Increased risk of gastrointestinal bleeding (see section 4.4).

Antidiabetics, e.g. sulphonylureas and insulin

Salicylates may increase the hypoglycaemic effect of antidiabetics. Thus, some downward re-adjustment of the dosage of the antidiabetic may be appropriate if large doses of salicylates are used. Increased blood glucose controls are recommended.

Digoxin and lithium

Acetylsalicylic acid impairs the renal excretion of digoxin and lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin and lithium is recommended when initiating and terminating treatment with acetylsalicylic acid. Dose adjustment may be necessary

Diuretics and antihypertensives

NSAIDs may decrease the antihypertensive effects of diuretics and other antihypertensive agents. Blood pressure should be well monitored.

Concomitant administration with ACE-inhibitors, angiotensin II receptor antagonists and calcium-channel blocker increases the risk of acute renal insufficiency in combination with high-dose ASA

Loop diuretics

Risk of acute renal failure due to the decreased glomerular filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended.

Patients concomitantly treated with verapamil and acetylsalicylic acid should be carefully monitored for signs of bleeding.

Carbonic anhydrase inhibitors (acetazolamide)

May result in severe acidosis and increased central nervous system toxicity.

Systemic corticosteroids

The risk of gastrointestinal ulceration and bleeding may be increased when acetylsalicylic acid and corticosteroids are co-administered (see section 4.4).

Methotrexate (used at doses <15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, may increase haematological toxicity of methotrexate due to decreased renal clearance of methotrexate by acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring should take place in the presence of even mildly impaired renal function, as well, as in elderly.

NSAIDs

Increased risk of ulcerations and gastrointestinal bleeding due to synergistic effects.

Ibuprofen

Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid 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).

Metamizole

Metamizole may reduce the effect of acetylsalicylic acid (aspirin) on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

Ciclosporin, tacrolimus

Concomitant use of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin and tacrolimus. The renal function should be monitored in case of concomitant use of these agents and acetylsalicylic acid.

Valproate

Acetylsalicylic acid has been reported to decrease the binding of valproate to serum albumin, thereby increasing its free plasma concentrations at steady state.

Phenytoin

Salicylate diminishes the binding of phenytoin to plasma albumin. This may lead to decreased total phenytoin levels in plasma, but increased free phenytoin fraction. The unbound concentration, and thereby the therapeutic effect, does not appear to be significantly altered.

Alcohol

Concomitant administration of alcohol and acetylsalicylic acid increases the risk of gastrointestinal bleeding.

4.6. Fertility, pregnancy and lactation

Pregnancy

Low doses (up to 100 mg/day):

Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.

Doses of 100-500 mg/day:

There is insufficient clinical experience regarding the use of doses above 100 mg/day up to 500 mg/day. Therefore, the recommendations below for doses of 500 mg/day and above apply also for this dose range.

Doses of 500 mg/day and above:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, acetylsalicylic acid should not be given unless clearly necessary. If acetylsalicylic acid is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, acetylsalicylic acid at doses of 100 mg/day and higher is contraindicated during the third trimester of pregnancy.

Breastfeeding

Low quantities of salicylates and of their metabolites are excreted into the breast milk. Since adverse effects for the infant have not been reported up to now, short-term use of the recommended dose does not require suspending lactation. In cases of long-term use and/or administration of higher doses, breastfeeding should be discontinued.

Fertility

For acetyl-salicylic acid ≥ 500 mg/day and equipotent derivates

There is some evidence that drugs that inhibit cyclooxygenase/prostaglandin synthesis may affect female fertility via an effect on ovulation. This effect is reversible after discontinuation of treatment.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed with Aspirin.

Based on the pharmacodynamic properties and the side effects of acetylsalicylic acid, no influence on the reactivity and the ability to drive or use machines is expected.

4.8. Undesirable effects

Tabulated list of adverse reactions

Side effects are grouped on the basis of System Organ Class. Within each system organ class the frequencies are defined as:

Very common:

Common:

Uncommon:

Rare:

Very rare:

Not known:

≥ 1/10

≥ 1/100, < 1/10

≥ 1/1.000, < 1/100

≥ 1/10.000, < 1/1.000

< 1/10.000

frequency cannot be estimated from the available data.

System organ class

Common

Uncommon

Rare

Not known

Blood and lymphatic system disorders

Increased bleeding tendencies

Thrombocytopenia, agranulocytosis, aplastic anaemia

Cases of bleeding with prolonged bleeding time such as epistaxis, gingival bleeding. Symptoms may persist for a period of 4–8 days after acetylsalicylic acid discontinuation. As a result there may be an increased risk of bleeding during surgical procedures.

Existing (haematemesis, melaena) or occult gastrointestinal bleeding, which may lead to iron deficiency anaemia (more common at higher doses).

Immune system disorders

Hypersensitivity reactions, angio-oedema, allergic oedema, anaphylactic reactions including shock.

Metabolism and nutrition disorders

Hyperuricemia, hypoglycaemia

Nervous system disorders

Intracranial haemorrhage

Headache, vertigo

Ear and labyrinth disorders

Reduced hearing ability; tinnitus

Vascular disorders

Haemorrhagic vasculitis

Respiratory, thoracic and mediastinal disorders

Rhinitis, dyspnoea

Bronchospasm, asthma attacks

Gastrointestinal disorders

Dyspepsia, nausea, vomiting, diarrhoea

Severe gastrointestinal haemorrhage,

Gastric or duodenal ulcers and perforation

Hepatobiliary disorders

Reye's syndrome

Hepatic insufficiency, hepatic enzyme increased

Skin and subcutaneous tissue disorders

Urticaria

Stevens-Johnson syndrome, Lyells syndrome, purpura, erythema nodosum, erythema multiforme

Renal and urinary disorders

Impaired renal function, acute renal failure

Reproductive system and breast disorders

Menorrhagia

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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Although considerable inter-individual variations are involved, it can be considered that the toxic dose is about 200 mg/kg in adults and 100 mg/kg in children. The lethal dose of acetylsalicylic acid is 25‑30 grams. Plasma salicylate concentrations above 300 mg/l indicate intoxication. Plasma concentrations above 500 mg/l in adults and 300 mg/l in children generally cause severe toxicity.

Overdose may be harmful for elderly patients and particularly for small children (therapeutic overdose or frequent accidental intoxications may be fatal).

Symptoms of moderate intoxications

Tinnitus, hearing disorders, headache, vertigo, confusion and gastrointestinal symptoms (nausea, vomiting and abdominal pain).

Symptoms of severe intoxications

Symptoms are related to severe disruption of the acid-base balance. In the first instance hyperventilation occurs, which results in respiratory alkalosis. Respiratory acidosis ensues due to suppression of the respiratory centre. In addition, metabolic acidosis occurs as a result of the presence of salicylate. Since younger children are often not seen until they have reached a late stage of intoxication, they are usually in the stage of acidosis.

Furthermore, the following symptoms may occur: feelings of restlessness, convulsions, hallucinations; pulmonary oedema; hyperthermia and perspiration, resulting in dehydration; and hypoglycaemia. Depression of the nervous system may lead to coma, cardiovascular collapse or respiratory arrest.

Treatment of overdose

If a toxic dose has been ingested, hospital admission is required.

Monitoring and treatment should follow standard principles for acetylsalicylic acid overdose (as recommended by national poisons information centres). In addition to general symptomatic therapy, including compensation of fluid loss, specific therapy including management of coagulation disturbances, alkalisation of urine and haemodialysis could be required in selected cases.

Activated charcoal may be given as a single dose (50 g for an adult, 1 g/kg body weight for children if the patient presents within 1 hour of ingestion of 125mg/kg or more salicylate, or any amount of methyl salicylate, providing it is safe to do so and the airway can be protected. Efficacy declines rapidly with time since ingestion but there may be some potential benefit from later use, especially following large ingestions. A second dose of charcoal may be warranted in patients whose plasma salicylate concentration continues to rise, suggesting delayed gastric emptying, or who have taken enteric coated preparations where absorption may be slower.

Other symptoms to be treated symptomatically.