Aspirin Enteric Coated Tablets 75mg – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Aspirin Enteric Coated Tablets 75mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains aspirin BP

75mg.

Excipient(s) with known effect

Lactose

Sucrose

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Enteric-coated tablet for oral administration.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the secondary prevention of thrombotic cerebrovascular or cardiovascular disease and following by-pass surgery. Owing to the delayed release of the aspirin imposed by the enteric coating, these tablets are not suitable for short term pain relief.

4.2 Posology and method of administration

Posology

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

The usual dosage for long term use is one to two tablets (75-150mg) to be taken once daily. In some circumstances a higher dose may be appropriate, especially in the short term, and up to 4 tablets (300mg) a day may be used on the advice of a doctor. 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.

Children:

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki’s disease). (see 4.4 ‘Special Warnings and Special Precautions for Use’).

Method of administration

For oral administration to adults only. Take the tablet with water, do not cut, chew or crush the tablet. Swallow whole.

4.3 Contraindications

• Hypersensitivity to salicylic acid compounds or prostaglandin synthetase inhibitors (e.g. certain asthma patients who may suffer an attack or faint and certain patients who may suffer from bronchospasm, rhinitis and urticaria), or to any of the excipients listed in section 6.1
• Active or history of peptic ulceration and/or gastric/ intestinal haemorrhage, or other kinds of bleeding such as cerebrovascular haemorrhages
• Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia or concurrent anticoagulant therapy
• Patients who are suffering from gout
• Severe hepatic impairment
• Severe renal impairment
• Doses >100 mg/day during the third trimester of pregnancy (see section 4.6);
• Methotrexate used at doses >15mg/week (see section 4.5).

4.4 Special warnings and precautions for use

Aspirin Enteric Coated Tablets 75mg is not suitable for use as an anti-inflammatory/analgesic/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 particularly during or after operative procedures (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.

Caution should be exercised in patients with allergic disease, impairment of hepatic or renal function (avoid if severe) and dehydration, 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.

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

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

The elderly may be more susceptible to the toxic effects of NSAIDs, including acetylsalicylic acid especially gastrointestinal bleeding and perforation which may be fatal. (see section 4.2). Where prolonged therapy is required, patients should be reviewed regularly.

Aspirin Enteric Coated Tablets 75mg are not recommended during menorrhagia where it may increase menstrual bleeding.

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. Use with caution before surgery, including tooth extraction. Patients should report any unusual bleeding symptoms to their physician.

Aspirin is to be used with caution in cases of hypertension and patients with a stomach ulcer or a history of stomach ulcers or duodenal ulcer or haemorrhagic episodes or 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.

Concomitant treatment with Aspirin and other drugs that alter haemostasis (i.e. anticoagulants such as warfarin, thrombolytic and 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).

The risk of hypoglycaemic effects with sulfonylureas and insulins may be potentiated with Aspirin Enteric Coated Tablets 75mg taken at over dosage (see section 4.5).

Aspirin should be avoided in late pregnancy and generally during breast feeding (see section 4.6).

This medicinal product contains lactose and sucrose. 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 Enteric Coated Tablets 75mg is contraindicated (see section 4.3).

Not recommended combinations:

Uricosuric agents, e.g. probenecid and 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 e.g. coumarin, heparin, warfarin and phenindione: 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. The bleeding time should be monitored (see section 4.4).

Antiplatelet agents (e.g. clopidogrel and dipyridamole) and selective serotonin re-uptake inhibitors (SSRIs; such as sertraline or paroxetine): Increased risk of gastrointestinal bleeding (see section 4.4).

Antidiabetics, e.g. sulphonylureas

Salicylics may increase the hypoglycaemic effect of sulphonylureas.

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. As for other NSAIDs concomitant administration with ACE-inhibitors increases the risk of acute renal insufficiency.

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.

Carbonic anhydrase inhibitors (acetazolamide):

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

Systemic Corticosteroids:

The risk of gastrointestinal bleeding and ulceration is 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.

Other non-steroidal anti-inflammatory drugs (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 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)

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.

Alcohol:

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

Phenytoin (Anti-epileptics):

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.

Valproate:

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

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 cardioprotection.

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 above 100 mg/ day and up to 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.

From the 20th week of pregnancy onward, acetylsalicylic acid use may cause

oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to acetylsalicylic acid for several days from gestational week 20 onward. Acetylsalicylic acid should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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 (see section 4.3). Doses up to and including 100 mg/day may only be used under strict obstetric monitoring.

Breast-feeding:

Low quantities of salicylates and of their metabolites are excreted in 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 breastfeeding. In cases of long-term use and/or administration of higher doses, breastfeeding should be discontinued.

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 grouped on the basis of System Organ Class. Within each system organ class the frequencies are defined as: 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) and not known (cannot be estimated from the available data).

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

Although considerable inter-individual variations are involved, it can be considered that the toxic dose is about 200mg/kg in adults and 100mg/kg in children. The lethal dose of acetylsalicylic acid is 25-30 grams. Salicylate poisoning is usually associated with plasma concentrations >300mg/L (2.5mmol/L). Plasma concentrations above 500mg/l in adults and 300mg/l in children generally cause severe toxicity. 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.

.

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

Symptoms

Common features include vomiting, nausea, abdominal pain, dehydration, tinnitus, vertigo, headache, deafness, sweating, warm extremities with bounding pulses. .

Symptoms of severe intoxications:

Some degree of acid-base disturbance is present in most cases. 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 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. Since younger children are often not seen until they have reached a late stage of intoxication, they are usually in the stage of acidosis. Acidosis may increase salicylate transfer across the blood brain barrier.

Furthermore, the following symptoms may occur: haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and noncardiac pulmonary oedema, hyperthermia and perspiration, resulting in dehydration, feelings of restlessness, convulsions and hallucinations.

Central nervous system features including confusion, disorientation, coma, convulsions, cardiovascular collapse or respiratory arrest are less common in adults than in children.

Treatme

nt of

overdos

e

If a toxic dose has been ingested, hospital admission is required. In the event of moderate intoxication, inducing the patient to vomit should be attempted.

If this fails, gastric lavage may be attempted during the first hour after ingestion of a substantial amount of the medicine.

Give activated charcoal (50g for adult, 1g/kg body weight for a child up to 12 years) 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 is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700mg/L (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.

Other symptoms to be treated symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Blood and blood forming organs – antithrombotic agents: platelet aggregation inhibitors excl. heparin ATC code: B01A C06

Mechanism of action

Aspirin inhibits platelet aggregation. Blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatosic lesions. Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesise new cyclooxygenase, which had been acetylated by acetylsalicylic acid.

The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%. Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7-10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption. Acetylsalicylic acid extends bleeding time on average by approximately 50 to 100%, but individual variations can be observed.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 h before or within 30min after immediate release aspirin dosing (81mg), a decreased effect of ASA 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: After oral administration, acetylsalicylic acid is rapidly absorbed from the gastrointestinal tract. However, a significant portion of the dosage is already hydrolysed to salicylic acid in the intestinal wall during the absorption process.

Distribution: Acetylsalicylic acid as well as the main metabolite salicylic acid, are extensively bound to plasma proteins, primarily albumin, and distributed rapidly into all parts of the body. Maximum plasma concentration is reached after 0.3 – 2 hours (total salicylate). The volume of distribution of acetylsalicylic acid is ca. 0.16 l/kg of body weight.

Biotransformation: Acetylsalicylic acid is rapidly metabolised to salicylic acid, with a half-life of 15-30 minutes. Salicylic acid is subsequently predominantly converted into glycine and glucuronic acid conjugates. Elimination kinetics of salicylic acid is dose-dependent, because the metabolism is limited by liver enzyme capacity. Thus, elimination half-time varies and is 2-3 hours after low doses (75 mg – 160 mg).

Excretion: Salicylic acid and its metabolites are predominantly excreted via the kidneys.

5.3 Preclinical safety data

The nonclinical safety profile of acetylsalicylic acid is well documented.

In experimental animal studies, salicylates have shown no other organ injury than renal damage. In rat studies, fetotoxicity and teratogenic effects were observed with acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in non-clinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications. Acetylsalicylic acid was extensively investigated with regard to mutagenic and carcinogenic effects. The results as a whole show no relevant signs for any mutagenic or carcinogenic effects in mice and rat studies.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose, starch, sucrose, talc, Eudragit L100-55, polyethylene glycol, hydroxypropyl methylcellulose and titanium dioxide (E171).

6.2 Incompatibilities

None.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

HDPE containers with HDPE lids (OTC packs, child resistant) containing 100 tablets,

or

Blister packs comprised of aluminium/PVC strips enclosed in an outer carton containing 28 or 56 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited

Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford

DA1 5BS

8 MARKETING AUTHORISATION NUMBER(S)

PL 40147/0008

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

27 January 1998

10 DATE OF REVISION OF THE TEXT

03/11/2025