ASPIRIN 81

Composition: Each enteric-coated tablet contains:
Acetylsalicylic acid. . . . . . . . . . . . . . . . . .81 mg
Presentation:
Box of 20 blisters x 10 enteric-coated tablets.
Indications:
Primary and secondary prevention of myocardial infarction, strokes.

Additional information

Dosage and administration

Dosage: The usual dose for long-term treatment is 1-2 tablets once daily. In some cases, the appropriate dose may be higher, especially in the short-term treatment and dose may be used up to 4 tablets per day as directed by doctor.
Administration: The tablets must be swallowed whole after meals, do not chew or crush them.

Contraindications

Hypersensitivity to salicylate derivatives and NSAIDs.
A history of asthma.
Gastroduodenal ulcers.
All forms of hemorrhage with visceral origin or acquired bleeding.
At risks of bleeding.
Glomerular filtration rate below 30ml/min and cirrhosis.
Patients who are recently suffering from gout.
Pregnant woman must take not more than 100mg of aspirin a day during the last trimester of pregnancy.

Warnings and precautions for use

Aspirin 81 is not suitable for use as an anti- inflammatory, analgesic, antipyretic.
Aspirin 81 should be used in patients aged 16 years and older. It is not recommended for use in patients under 16 years unless the expected benefits outweigh the potential risks. Acetylsalicylic acid may be a contributory factor in the causation of Reye's syndrome in some children.
Aspirin 81 should be used with caution before surgery, temporary discontinuation of treatment may be necessary. There is an increased risk of haemorrhage particularly during or after operative procedures (even in minor surgery, e.g. tooth extraction).
Aspirin 81 is not recommended during period menstrual bleeding may be increased.
Aspirin 81 should be used with caution in hypertensive patients and those with a history of gastric or duodenal ulcers or bleeding or patients who are being treated 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 If gastrointestinal bleeding or ulceration occurs the treatment should be withdrawn.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.
Acetylsalicylic acid may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, 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. Aspirin 81 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, including acetylsalicylic acid especially gastrointestinal bleeding and perforation which may be fatal. Where prolonged therapy is required, patients should be reviewed regularly.
Concomitant treatment with Aspirin 81 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. 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.
Acetylsalicylic acid should be avoided in late pregnancy and generally during breast feeding.
Aspirin 81 in low doses reduces uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks.
Overdose of Asprin 81 may potentiate hypoglycaemic effect of sulfonylureas and insulin.
This medicine contains:
. Tartrazine (E 102): Which can cause allergic reactions.
. Wheat starch: Aspirin 81 should not be used if you are allergic to wheat (different from Celiac disease).

Recommendation for pregnancy and breastfeeding

Pregnant:
Low doses (up to 100mg/day): Clinical studies indicate that doses up to 100mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.
Doses of 100- 500mg/day: There is insufficient clinical experience regarding the use of doses above 100mg/day up to 500mg/day. Therefore, the recommendations below for doses of 500mg/day and above apply also for this dose range.
Doses of 500mg/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 100mg/day and higher is contraindicated during the third trimester of pregnancy.
Lactation:
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 breastfeeding.

Effects on ability to drive and use machines

There have been no studies on the effects of Aspirin 81 on ability to drive or operate machinery.

Interactions, incompatibilities of medicine

Contraindicated combinations:
Methotrexate (used at doses >15mg/week): The combination of methotrexate and acetylsalicylic acid enhances haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15mg/week) with Aspirin 81 is contraindicated.
Not recommended combinations:
Uricosuric agents, e.g. Probenecid.
Salicylates reverse the effect of probenecid; the combination should be avoided.
Combinations requiring precautions for use or to be taken into account:
Anticoagulants e.g. Coumarin, heparin, warfarin: 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.
Anti-platelet agents (e.g Clopidogrel and dipyridamole) and selective serotonin re-uptake inhibitors (such as: Sertraline or paroxetine): Increased risk of gastrointestinal bleeding.
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. 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 (e.g. Acetazolamide): May result in severe acidosis and increased central nervous system toxicity.
Glucocorticoids: The risk of gastrointestinal ulceration and bleeding may be increased.
Methotrexate (used at doses <15 mg/week): The combination of 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 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.
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.
Antacids: The excretion of acetylsalicylic acid is increased by alkaline urine caused by antacids. Alcohol: Concomitant administration of alcohol and acetylsalicylic acid increases the risk of gastrointestinal bleeding.

Undesirable effects (ADRs)

Common, ADR >1/100
Gastrointestinal: Nausea, vomiting, dyspepsia, epigastric discomfort, heartburn, gastric pain, peptic ulcers.
Central nervous system: Fatigue.
Skin: Rash, urticaria.
Hematologic: Hemolytic anemia.
Musculoskeletal: Muscle weakness.
Respiratory: Dyspnea.
Other: Anaphylaxis.
Uncommon, 1/1000 < ADR < 1/100
Central nervous system: Insomnia, restlessness, irritability.
Endocrinology and metabolism: Iron deficiency.
Hematologic: Occult bleeding, prolonged bleeding time, leukopenia, thrombocytopenia, anemia.
Hepatic: Hepatotoxicity.
Kidney: Impaired kidney function.
Respiratory: Bronchospasm.
Guidelines for ADR management:
Symptoms of ADRs on the central nervous system can resolve completely within 2 to 3 days after aspirin withdrawal. If there are symptoms of dizziness, tinnitus, hearing loss or liver damage, aspirin use therapy must be stopped. In the elderly, the lowest effective aspirin dose for the shortest possible time should be used. Therapy used for the treatment of aspirin anaphylaxis is similar to that of acute anaphylactic rections. Adrenaline is selected and urticaria and angioedema can generally be easily managed.

Overdose and management

Overdose:
Large-dose acetylsalicylic acid ingestion can lead to deep and rapid breathing, tinnitus, deafness, vasodilation, sweating.
Management:
Empty the patient's stomach immediately by inducing vomiting (protection of the airway against aspiration) or gastric lavage, give oral activated charcoal. Vital functions should be monitored and supported: Treatment of high fever; fluid and electrolyte infusion, correction of acid-base imbalances; treatment of ketone accumulation symptoms; maintaining appropriate plasma glucose levels.
Urine alkalinization enhances salicylate elimination.
Haemoperfusion, haemodialysis or peritoneal dialysis may be performed in severe overdose, if necessary.
Pulmonary edema, convulsions should be monitored and appropriate therapies should be carried out, if necessary.
Blood transfusion or vitamin K can be administered to treat bleeding, if necessary.

Pharmacodynamic properties

Acetylsalicylic acid inhibits irreversibly cyclooxygenase, leads to inhibiting the synthesis of prostaglandin. Cells capable of synthesizing new cyclooxygenase may continue synthesizing prostaglandin after the concentration of acetylsalicylic acid is decreased. Platelets are cells that have no nucleus, they are unable to synthesize new cyclooxygenase, therefore cyclooxygenase is inhibited irreversibly until new platelets are formed. Thus, acetylsalicylic acid inhibits irreversibly platelet aggregation, until new platelets are produced.
Acetylsalicylic acid also inhibits the production of prostaglandins in the kidney. The production of prostaglandins in the kidneys is less physiologically important in subjects with normal kidney function, but it has important role in maintaining renal blood flow in patients with chronic renal failure, heart failure, liver failure or disorders of plasma volume. In these patients, the effect of aspirin on inhibiting renal prostaglandin synthesis can lead to acute renal failure, fluid retention and acute heart failure.

Pharmacokinetic properties

After oral administration, acetylsalicylic acid is rapidly and highly absorbed. While absorbed in the gut wall, as well as in the liver and blood, acetylsalicylic acid is hydrolyzed to salicylic acid, which has the same pharmacological properties as acetylsalicylic acid.
Oral bioavailability: 68% ± 3.
Plasma protein binding: 49%. Increase in blood urea level may reduce plasma protein binding.
Clearance: 9.3 ml/min/kg ± 1.1. Clearance changes in the elderly and patients with cirrhosis.
Biological half-life: 0.25 hour ± 0.03. Biological half-life changes in patients with hepatitis.
Renally excreted primarily in the form of free salicylic acid and conjugated metabolites.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 24 months from the manufacture date.
Quality specification: In house specification.