4.1. Therapeutic indications

For the relief of mild to moderate pain in headaches, including migraine headaches, toothache, neuralgia, sciatica, period pains and sore throats.

Reduction of temperature in feverishness, influenza and colds.

Reduction of inflammation in rheumatism and lumbago.

4.2. Posology and method of administration

Oral administration after dissolution in water.

Adults (including children 16 years and over): Two to three tablets every 4 -6 hours. Do not exceed 12 tablets in 24 hours.

Do not give to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

There is no indication that dosage need be modified in the elderly.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 3 days.

Hepatic Impairment: Patients with hepatic impairment should seek the advice of a doctor before taking this product (see section 4.4).

Renal Impairment: Patients with renal impairment should seek the advice of a doctor before taking this product (see section 4.4).

Elderly population: Non-steroidal anti-inflammatory drugs should be used in caution in elderly patients who are more prone to adverse events (see section 4.4).

4.3. Contraindications

Hypersensitivity to acetylsalicylic acid or to any of the excipients listed in section 6.1.

Hypersensitivity to other non-steroidal anti-inflammatory drugs.

Nasal polyps associated with asthma.

Should not be given to patients suffering from a previous history of peptic ulceration or active peptic ulceration or bleeding disorders including haemophilia.

Disprin contains soy protein. If you are allergic to peanut or soya do not use this medicinal product.

Severe hepatic impairment.

Severe renal impairment.

Severe heart failure.

Children aged under 16 years due to a possible risk of Reye's syndrome, unless specifically indicated (see section 4.4).

During last trimester of pregnancy (see section 4.6).

Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

This medicine contains less than 1mmol sodium (23 mg) per dose, that is to state essentially 'sodium-free'.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal effects: NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8).

Gastrointestinal bleeding, ulceration or perforation which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Acetylsalicylic acid decreases platelet adhesiveness and increases bleeding time. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as clopidogrel and ticlopidine (see section 4.5).

SLE and mixed connective tissue disease: Systemic lupus erythematosus and mixed connective tissue disease, due to increased risk of aseptic meningitis (see section 4.8).

Dermatological effects: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Acetylsalicylic acid should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Paediatric use: There is a possible association between acetylsalicylic acid 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 acetylsalicylic acid should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

Cardiovascular effects: Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension, and oedema have been reported in association with NSAID therapy.

Respiratory effects: Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Renal: Caution is advised in patients with renal impairment (see section 4.8).

Hepatic: Caution is advised in patients with hepatic impairment (see section 4.8).

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Other NSAIDs: The use with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Impaired female fertility: May cause impairment of female fertility (see section 4.6).

Patients with gout: The product should not be given to patients with gout, as serum urate may be increased, unless recommended by a healthcare professional.

Surgical procedures: Acetylsalicylic acid should be stopped several days before scheduled surgical procedures due to increased bleeding time.

Laboratory tests: Acetylsalicylic acid and other salicylates can interfere with thyroid function tests.

Caution should be implemented in patients with a history of other bleeding events such as intracranial haemorrhage, due to the increased risk of intercranial haemorrhage with acetylsalicylic acid use.

Overuse headaches: Use of NSAIDs or analgesics for 15 or more days per month, for 3 months or more, increases your risk of medication overuse headache.

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

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Calcium channel blockers: Reduced hypotensive effects, increased anti-platelet effects rarely resulting in prolonged bleeding time.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

Varicella vaccine: Avoid use of acetylsalicylic acid in varicella vaccine recipients due to a possible association with Reye's syndrome.

Antihypertensives (ACE inhibitors and Angiotensin II Antagonists) and diuretics: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Anti-coagulants: Aspirin may enhance the effects of anticoagulants and inhibit the effects of uricosurics.

Ibuprofen: 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).

Other NSAIDs or other salicylates including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Ciclosporin: Increased risk of nephrotoxicity with NSAIDs.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine.

Metoclopramide & domperidone: May increase the rate of absorption of acetylsalicylic acid.

Valproate: Acetylsalicylic acid may increase valproate levels resulting in valproate toxicity.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Uricosurics: Acetylsalicylic acid may inhibit the effects of uricosurics.

Mifepristone: NSAIDs can reduce the effect of mifepristone.

Methotrexate: Decreased elimination of methotrexate.

Carbonic anhydrase inhibitors e.g. Acetazolamide: May result in severe acidosis and increased central nervous system toxicity.

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

Sulfonylurea hypoglycaemic drugs: Acetylsalicylic acid may increase the activity of sulfonylurea hypoglycaemic drugs.

Zafirlukast: The activity of zafirlukast may be increased following acetylsalicylic acid administration.

Phenytoin: Acetylsalicylic acid may increase the effects of phenytoin.

4.6. Pregnancy and lactation

Pregnancy

The product is contraindicated in the third trimester of pregnancy (see section 4.3) and should be avoided during the first and second trimesters.

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.

Breast-feeding

Use of the product is contraindicated in breast-feeding. Acetylsalicylic acid given in breast-feeding mothers may pose a risk of Reye's syndrome in nursing infants (see section 4.3).

Fertility

There is some evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

4.7. Effects on ability to drive and use machines

None known.

4.8. Undesirable effects

Adverse events which have been associated with acetylsalicylic acid are given below, tabulated by system organ class and frequency. Frequencies are defined as: Very common (≥1/10); Common (≥1/100 and <1/10); Uncommon (≥1/1000 and <1/100); Rare (≥1/10,000 and <1/1000); Very rare (< 1/10,000); Not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

System Organ Class

Frequency

Adverse Events

Blood and Lymphatic System Disorders

Not known

Hypoprothrombinaemia, thrombocytopenia, aplastic anaemia, agranulocytosis, pancytopenia

Immune System Disorders

Not known

Hypersensitivity1, pyrexia, urticaria, pruritus, angioedema1

Metabolism and Nutrition Disorders

Not known

Sodium retention, fluid retention

Nervous System Disorders

Not known

Aseptic meningitis

Cardiac Disorders

Not known

Cardiac failure, oedema

Vascular Disorders

Not known

Hypertension, haemorrhage intercranial

Respiratory, Thoracic and Mediastinal Disorders

Very rare

Aspirin-exacerbated respiratory disease

Not known

Bronchospasm, asthma, dyspnoea, rhinitis1

Gastrointestinal Disorders

Not known

Gastrointestinal haemorrhage, gastrointestinal disturbances2, peptic ulcer, melaena, haematemesis, mouth ulceration

Hepatobiliary Disorders

Not known

Hepatotoxicity

Skin and Subcutaneous Tissue Disorders

Not known

Stevens-Johnson syndrome, toxic epidermal necrolysis, rash1

Renal and Urinary Disorders

Not known

Blood uric acid increased

Investigations

Not known

Bleeding time prolonged, platelet adhesiveness decreased

¹ Hypersensitivity reactions may consist of (a) respiratory tract reactivity, including asthma, bronchospasm (potentially severe, even fatal) and dyspnoea; (b) various skin reactions, including urticaria, angioedema, pruritus, other skin eruptions, and more rarely bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

² Gastrointestinal effects may include nausea, vomiting, dyspepsia, gastritis, diarrhoea, and constipation.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate, fever, dizziness and hyperventilation. Some degree of acid-base disturbance is present in most cases. Headache, nausea, restlessness, and ketosis may also occur.

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

Uncommon features 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. In severe cases, respiratory failure and cardiovascular collapse are also possible.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 125 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, which is achieved by the administration 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. Fluid and electrolyte management should be used to correct acidosis, hyperprexia, hypokalaemia and dehydration.

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