Aspirin 75mg Gastro-Resistant Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aspirin 75mg Gastro-resistant Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Aspirin 75 mg.
3 PHARMACEUTICAL FORM
Gastro resistant tablet
White circular tablet, plain on both sides.
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. The usual dosage, for long-term use, is 75mg-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. Take the tablet with water, do not cut, chew or crush the tablet. Swallow whole.
Children:
Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki’s disease).
Gastro-intestinal irritation may be reduced by taking aspirin with or immediately after food.
4.3
Contraindications
• Hypersensitivity to aspirin or any of the excipients (see section 6.1) In patients with a history of hypersensitivity to aspirin (or any of the excipients) or any other NSAIDs and in patients in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated by aspirin or other NSAIDs.
• Active peptic ulceration or history of peptic ulceration
• Haemophilia, other coagulopathies or concurrent anticoagulant therapy
• Gout
• Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki’s disease).
• Doses > 100mg/day during the third trimester of pregnancy.
4.4 Special warnings and precautions for use
Caution should be exercised in patients with asthma, allergic disease, , impairment of hepatic or renal function (avoid if severe), impaired cardiac function, uncontrolled hypertension and-dehydration, dyspepsia and in patients with nasal polyps or a history of nasal polyps.
Aspirin should be used with caution in patients with infections, since symptoms such as fever and inflammation may be masked.
The elderly may be more susceptible to the toxic effects of salicylates. Continuous prolonged use of aspirin should be avoided in the elderly because of the risk of gastrointestinal bleeding.
Caution should be taken in patients with glucose-6-phosphate dehydrogenase deficiency as haemolytic anaemia may occur.
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. Renal, hepatic and haematological status should be monitored during prolonged and high dose aspirin therapy.
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).
Patients with a history of peptic ulceration or coagulation abnormalities should use this product with care.
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.
Before commencing long-term aspirin 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.
4.5 Interaction with other medicinal products and other forms of interactions
Alcohol: Some of the effects of aspirin on the gastrointestinal tract are enhanced by alcohol.
Anaesthetics: Aspirin may potentiate the effects of thiopental anaesthesia.
Antacids and adsorbents: The excretion of aspirin is increased in alkaline urine; kaolin possibly reduces absorption.
Anti-coagulants: Aspirin may enhance the effects of anti-coagulants (e.g. increased risk of bleeding with concomitant heparin; increased risk of major bleeding [cerebral/intracranial haemorrhage] with concomitant streptokinase); concurrent use is contraindicated (see Section 4.3).
Anti-epileptics: May enhance the effects of phenytoin and sodium valproate. Increased risk of bleeding when aspirin and sodium valproate or valproic acid used concomitantly.
Antimetabolites: The activity of methotrexate may be markedly enhanced and its toxicity increased.
ACE Inhibitors: Aspirin may reduce the antihypertensive effects of ACE inhibitors. Risk of renal impairment when > 300mg/day aspirin is given concomitantly with ACE inhibitors, particularly in patients with poor renal perfusion.
Angiotensin-II receptor antagonists: Concomitant administration with aspirin at doses >3g may reduce the antihypertensive effect of angiotensin-II antagonists. Risk of renal impairment with >300mg/day aspirin, particularly in patients with poor renal perfusion.
Antibacterials: The toxicity of sulphonamides may be increased.
Antiemetics: Metoclopramide enhances the effects of aspirin by increasing the rate of absorption.
Antiplatelet drugs: Possibility of increased antiplatelet effect, with abnormal bruising and prolonged bleeding time, with clopidogrel or ticlopidine.
Ascorbic acid: Absorption of ascorbic acid may be reduced.
Calcium channel blockers: Possibility of increased antiplatelet effect, with abnormal bruising and prolonged bleeding time, with calcium channel blockers such as verapamil.
Corticosteroids: The risk of gastrointestinal bleeding and ulceration is increased. Corticosteroids reduce the plasma salicylate concentration., however, salicylate toxicity may occur when corticosteroids are withdrawn in patients also taking aspirin.
Diuretics: Antagonism of the diuretic effect of sprionolactone. Reduced excretion of acetazolamide with an increased risk of toxicity. Salicylate intoxication has occurred in patients on high dose salicylate regimens and carbonic anhydrase inhibitors.
Gold Compounds: May increase risk of aspirin-induced liver damage.
Hypoglycaemic agents: Aspirin may enhance the effects of insulin and oral hypoglycaemic agents.
Leukotriene antagonists: The plasma concentration of zafirlukst is increased.
Mifepristone: The manufacturer of mifepristone recommends that aspirin should be avoided until eight to twelve days after mifepristone has been discontinued.
Other non-steroidal anti-inflammatory drugs (NSAIDs): Concurrent administration can increase side effects, although plasma concentrations of some other NSAIDs (e.g. indometacin, fenoprofen) may be reduced. 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).
Thyroid function tests: Aspirin may interfere with thyroid function tests.
Uricosurics: Effect of probenecid and sulfinpyrazone reduced. Uricosuric effects of aspirin reduced by phenylbutazone.
Vasodilators: Daily aspirin should not exceed 80mg/day when given with cilostazol.
4.6 Pregnancy and lactation
Pregnancy
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, acetyl salicyclic acid should not be given unless clearly necessary. If acetylsalicyclic 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-hydroaminiosis; 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.
• inhibiton of uterine contractions resulting in delayed or prolonged labour.
Consequently, acetylsalicyclic acid at doses of 100mg/day and higher is contraindicated during the third trimester of pregnancy.
Lactation:
Aspirin should be avoided during breast feeding - possible risk of Reye’s syndrome
4.7 Effects on ability to drive and use machines
Aspirin does not usually affect the ability to drive or operate machinery.
4.8 Undesirable effects
Side effects are generally mild and infrequent:
Blood disorders: Aspirin increases bleeding time, decreases platelet adhesiveness and, in large doses, may cause hypoprothrombinaemia. It may also cause other blood disorders including thrombocytopenia, aplastic anaemia, agranulocytosis and pancytopenia. Haemolytic anaemia can occur in patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Immune system: Aspirin may precipitate bronchospasm and induce dyspnoea, asthma attacks, rhinitis, angioedema , urticaria, rash, or other hypersensitivity in susceptible individuals.
Gastro-intestinal: Diarrhoea. Haematemesis and/or melaena may occur.
Hepatobiliary: Increased aminotransferase levels, usually reversible on withdrawal; dose-dependent focal hepatic necrosis.
Renal and urinary disorders: Haematuria may occur.
Skin: Skin reactions, including Stevens-Johnson syndrome or toxic epidermal necrolysis, may occur in susceptible patients.
4.9 Overdose
Salicylate poisoning is usually associated with plasma concentrations >350mg/L (2.5mmol/L) Most adult deaths occur in patients whose concentrations exceed 700mg/L (5.1mmol/L). Single doses less than 100mg/kg are unlikely to cause serious poisoning.
Symptoms
Common features include nausea, vomiting, dehydration, headache, tinnitus, vertigo, dizziness, deafness, sweating, warm extremities with bounding pulses, restlessness, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.
A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH ( normal or reduced hydrogen ion concentration) is usual in adults or children over the age of four years. In children 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. Cardiovascular collapse and respiratory failure may also occur.
Treatment
Give activated charcoal if an adult presents within one hour of ingestion of more than 250mg/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.
Haemodialysis or haemoperfusion are effective methods of removing salicylate from plasma, however, haemodyalisis is the treatment of choice for severe poisoning and should be considered in patients with plasma-salicylate concentrations mg/litre (5.1mmol/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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Aspirin has strong analgesic, anti-inflammatory and anti-pyretic activity. It is also used for its anti-thrombotic actions. Once 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.
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 400 mg was taken within 8 hours before or within 30 minutes after immediate release aspirin (81 mg), 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.
Blood concentration: Single and multiple 100 mg doses of enteric- coated aspirin give systemic bioavailabilities of between 15% and 20% of that seen with immediate release aspirin preparations. Cmax of aspirin for several enteric - coated preparations has been shown to be approximately 100 - 200 mg/ml with a half - life of approximately 1.7 hours. Plasma concentrations of salicylic acid increase disproportionately with dose - a 325 mg dose having a half-life of 2-3 hours and higher doses showing lower plasma concentrations in the presence of an increased half-life due to a disproportionate increase in volume of distribution.
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.
Excretion: Excreted in the urine mainly as salicyluronic acid. Salicylate reabsorbed by renal tubules in acid wine, and alkaline diuresis will increase the rate of excretion; 85% of dose excreted as free salicytate.
5.3 Preclinical safety data
None applied on the basis of the active ingredient being a well known and marketed compound with an established efficacy and side effect profile. The excipients are also commonly used ingredients made to Ph. Eur. and USP standards.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Potato Starch
Calcium hydrogen phosphate dihydrate
Microcrystalline cellulose
Talc
Methacrylic acid - ethylacrylate - co-polymer (1: 1) (also contains: Sodium Lauryl Sulphate and Polysorbate)
Macrogol
30% Simethicone emulsion
6.2 Incompatibilities
Aspirin is pharmaceutically incompatible with iron salts and alkalis.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original container in order to protect from moisture.
6.5 Nature and contents of container
Aluminium / PVC blister.
28, 32, 56 and 84 pack sizes.
6.6 Special precautions for disposal
No special conditions.
MARKETING AUTHORISATION HOLDER
7
Wockhardt UK Ltd Ash Road North Wrexham Industrial Estate Wrexham LL13 9UF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0014
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/02/1998
10 DATE OF REVISION OF THE TEXT
15/01/2015